2. WHAT IS PHARMACOKINETICS?
• Pharmaco = Drugs
Kinetics=Motion
• Study of Absorption, Distribution,
Metabolism and Elimination of Drugs in the
Body
• How the Body will handle the drug
3. Pharmacokinetics
ABSORPTION
● IS THE TRANSFER OF DRUGS FROM THE SITE OF
ADMINISTRATION TO THE SYSTEMIC CIRCULATION
DISTRIBUTION
● MOVEMENT OF DRUG THROUGHOUT THE BODY
PERMEATION
● passing through different barriers that separate body
compartments
4. METABOLISM
• TRANSFORMATION OF A DRUG TO A
MORE POLAR AND MORE READILY
EXCRETED PRODUCT
ELIMINATION
• REMOVAL OF DRUG FROM THE BODY
6. • Determined by:
A. Properties of a Drug
Physical nature of drug
Water or Lipid Solubility, Ionization etc.
B. Therapeutic Objectives
Desirability of Rapid Onset of Action or the need
for long term or restriction to a local site
7. Properties of a Drug
•Physical nature of drugs
• Solid (aspirin, atropine)
•Liquid ( nicotine, ethanol)
• Gaseous (nitrous oxide)
8. Properties of a Drug
•Drug size
• 100 to 1000 molecular weights
• (the lower limit is for specificity of action)
• (the upper limit, drugs must be able to move
within the body ( from the site of
administration to the site of action )
9. Properties of a Drug
• Drug Reactivity and Drug-Receptor Bonds
• Covalent
• Very strong, not reversible under biological conditions
acetylsalicylic acid(aspirin) and COX not readily broken)
• Electrostatic
• Hydrophobic
10. Properties of a Drug
• Drug Reactivity and Drug-Receptor Bonds
• Covalent
• Electrostatic
• More common and weaker than covalent bonds.
• Vary from relative strong linkages to weaker hydrogen
bonds and very weak induced dipole interactions such
as van der Waals forces.
• Hydrophobic
11. Properties of a Drug
• Drug Reactivity and Drug-Receptor Bonds
• Covalent
• Electrostatic
• Hydrophobic
• Quite weak and important in the interactions
of highly lipid-soluble drugs.
12.
13. • Enteral – passes through the mouth and GIT
• Parenteral – administered anywhere else in the body except
mouth and GIT
• Inhalation – passes through the pulmonary tract
• Intranasal – within the nasal cavity
• Intrathecal – administered in the spinal area
• Topical – surface of skin or mucosa
• Transdermal – patch on the skin
15. ENTERAL
•ORAL ROUTE (PO=per orem)
• Most commonly used route of drug
administration
• Safest, most convenient and most
economical
16. ORAL ROUTE (PO per orem)
Advantages:
• Patient acceptance is good because the
technique itself is painless
• Does not require a trained personnel to
administer the drug
17. ● Convenience and low cost with respect to other modes of
therapy are especially prominent for drugs that must be
given several times daily on a long-term basis
• Oral route is safe because absorption is slow
• Allergic reactions are less likely to occur
18. Disadvantages:
• Drug action is slow, thus not suitable for emergencies
• Incapability to absorb some drugs, due to their physical
characteristics
• Unpalatable and other irritant drugs cannot be
administered
• Can not be used for unconscious and uncooperative
patient
• May not be useful in the presence of vomiting and
diarrhea.
• Metabolic inactivation or complex formation may also
occur before the drug has a chance to reach the systemic
circulation
19. ENTERAL
SUBLINGUAL ROUTE
• Placed under the tongue, where they rapidly dissolve and are
absorbed quickly in the general circulation.
• Advantages:
• Rapid onset of action
• Degradation and metabolism of the drugs in the stomach and
liver is avoided
• Nitroglycerin ( angina pectoris )
• VASODILATOR
• Oxytocin
20. RECTAL ROUTE
• Drug is administered on the rectum
• 50% bypasses the portal circulation
biotransformation of drugs by the liver is
minimized
• Advantages: prevents destruction of the drug by
intestinal enzymes or by low pH in the stomach
21. •PARENTERAL – administration of drug directly into the
tissues or blood without crossing the GIT
ADVANTAGES:
• Rapid action of drug
• Can be employed in unconscious/ uncooperative
patient
• Drugs, which are modified by alimentary juices and
liver can be given in this route
• Drugs, which are not absorbed in small intestine or
irritate the stomach can be administered by this route
22. •PARENTERAL – administration of drug directly
into the tissues or blood without crossing the
GIT
DISADVANTAGES:
• Less safe, more expensive
• Inconvenient (painful) for the patient
• Self medication is difficult
• Chances of local injury at the site of injection
24. PARENTERAL ROUTES
SUBCUTANEOUS
• Constant and slow absorption to provide sustained effect
• Site of injection: outer surface of arm or outer surface of thigh
• Drugs: insulin, adrenaline, morphine and certain hormonal
preparation
• Dermojet – drug is provided from a microfine orifice using a high
velocity jet
• Pellet implantation – provides sustained release of the drug for
weeks and months
25. PARENTERAL ROUTES
INTRAMUSCULAR
• Site of injection: deltoid, triceps, gluteus
maximus, rectus femoris
• Soluble substances, mild irritants and
suspension
• Drugs: Hepatitis B vaccine ,Flu vaccine
• Rate of absorption is reasonably uniform and
the onset of action is rapid
26. PARENTERAL ROUTES
INTRAVENOUS
• Injected directly into a vein which produce rapid
action
• Most effective
• Most dangerous route
• Best for emergency when a rapid action is required
and infusion of large amounts of fluids (to overcome
dehydration) or to supply nutrition to patient who
can not take food/ fluid orally.
27. PARENTERAL ROUTES
INTRAARTERIAL
• Useful in diagnostics by which arterial blood
sample
may be withdrawn for blood gas studies.
• E.g. certain cytotoxic compounds are administered
by intraarterial perfusion in localised malignancies
28. PARENTERAL ROUTES
INTRADERMAL
• Injected into the skin raising a bleb
• For Vaccination (e.g. BCG vaccine)
• For testing sensitivity of certain drugs
(e.g. penicillins, lidocaine)
29. PARENTERAL ROUTES
INTRATHECAL/ INTRASPINAL
• Injected on the spinal subarachnoid space
• For local rapid effects of drugs on the meninges or
cerebrospinal axis.
• Spinal anesthesia or for introduction of a radiopaque
contrasting medium into the subarachnoid space for
visualizing the spinal cord during radiographs
32. PARENTERAL ROUTES
INTRACARDIAC
•In sudden cardiac arrest and other cardiac
emergencies drug like (epinephrine/adrenaline) is
directly injected into the heart using a long needle in
the left fourth intercostal space close to the sternum
36. Absorption of drugs
- Transfer of drug from its site of administration to the
bloodstream
- For a drug to be absorbed, reach its site of action and
eventually be eliminated, it must cross one or more
membrane barriers.
(PERMEATION)
37. Membranes
•Wall of Capillaries
• Pores between the cells are larger than most
drug
molecules, allowing them to pass freely, without
lipid solubility being a factor
38. Membranes
Cell Membranes
• Barrier between aqueous compartments in the body
• this barrier is permeable to many drug molecules
• Depends on Lipid Solubility and size of drug molecule
• Small pores, 8 angstroms, permit small molecules
such as alcohol and water to pass through
39. Membranes
Cell Membranes
• Epithelial barrier- GI mucosa/ Renal Tubule – cells tightly
interconnected molecule needs to traverse two cell
membranes (inner and outer) to pass from one side to
other
• Vascular endothelium – differs with anatomical
disposition and permeability. Gaps between endothelial
cells are packed with loose matrix of protein which acts as
filters retaining large molecules.
40. Membranes
Cell Membranes
• Special areas such as placenta and brain where
junctions are tight and encased in impermeable layer
of pericytes that prevents harmful things to traverse.
• Liver and Spleen endothelium is discontinuous
allowing free passage b/w cells.
• Fenestrated epithelium occurs in Endocrine Gland
facilitating transfer of hormones to blood stream
41. PASSIVE DIFFUSION
• drug moves down its electrochemical gradient
when crossing the membrane
•2 types
• Simple Diffusion
• Facilitated Diffusion
42. PASSIVE DIFFUSION
Simple Diffusion
• FROM HIGHER CONCENTRATION TO LOWER
CONCENTRATION
• Lipid soluble drugs readily pass through biological
membranes
• Water soluble drugs through aqueous channels
44. PASSIVE DIFFUSION
Ionization
• absence of ionic charge
• one major factor favoring lipid solubility. Simple ions
and charged molecules are stabilized in water by the
hydration shells that surround them, a consequence of
the tendency of charged species to orient polar
molecules.
45. PASSIVE DIFFUSION
Ionization
IONIZED - POLAR - WATER SOLUBLE
UNIONIZED - NON-POLAR - LIPID SOLUBLE
• No matter how lipid soluble an agent is, it will never cross
a membrane if it cannot first dissolve in the extracellular
fluid and be carried to the structure.
46. PASSIVE DIFFUSION
Lipid/water partition coefficient
• Usually expressed as the oil/water partition coefficient and
it is a measure of the relative solubility of a solute in an
organic phase vs. water.
• drug with higher L/W partition coefficient are said to be
lipophilic ( readily enters the lipid phase of the membrane )
47. ACTIVE TRANSPORT
• carrier-mediated transfer of a drug against its
electrochemical gradient. In addition, it requires
the
expenditure of energy (ATP/NADPH) and may be
blocked by inhibitors of cellular metabolism.
48. •Absorption of drugs
A. Transport of drug from GI tract
B. Effect of pH on drug absorption
C. Physical factors influencing absorption
49. Transport of drug from GI tract
• Drugs taken orally may be absorbed along the entire
alimentary canal, but the relative degree of contact with the
mucosa determines the amount of uptake in each segment.
• Oral and esophageal mucosa are exposed briefly
• Colon plays no role in the uptake of orally administered drug
with the exception of sustained release drug
• Bulk of drugs are absorbed in the stomach and small
intestines.
50. Transport of drug from GI tract
• Influence of pH
• Absorption is favored when the drug ingested is
lipid soluble.
• The pH of the surrounding medium affects the
degree of ionization and drug absorption
• H+ concentrations of the stomach and small
intestine diverge widely
51. Transport of drug from GI tract
• Influence of pH
• Most drugs are either weak acid or weak bases therefore
they are part ionized and unionized. The ionized portion is
charged which attracts water molecules, Thus forming large
complexes. These complexes cannot cross the membrane
because they are less lipid soluble. (the ionized part of the
drug cannot cross
the membrane)
52. Transport of drug from GI tract
• Influence of pH
• Aspirin 3.49 pKa(negative log dissociation constant)
• In gastric juice (pH 1 to 3), aspirin remains largely
unionized and its passage across the stomach
mucosa to the bloodstream is favored. However in
the plasma with a pH of 7.4, the drug becomes
ionized to such an extent that return of the drug to
the GIT is prevented by the low lipid solubility of the
anionic species.
53. Transport of drug from GI tract
• Influence of pH
• Henderson-Haselbach equation represents the relation of
pH, pKa and the degree of ionization of the drug
• Where,pH (of the medium) is the negative log of
the hydrogen ion concentration
• pKa (of the drug) is the pH of the medium at
which 50% of the drug is ionized and 50% is
unionized
54. Transport of drug from GI tract
• Influence of pH
• What this equation tells you:
• A WEAK ACID IN AN ACIDIC MEDIUM/ENVIRONMENT IS NON-
IONIZED
• A WEAK BASE IN A BASIC MEDIUM IS NONIONIZED
• ION TRAPPING
• When an acidic drug is in a basic medium, it
remains in that compartment since it is non diffusible
• When a basic drug is in an acidic medium, it
remains in that compartment since it is nondiffusible.
55. Transport of drug from GI tract
Mucosal Surface Area
• Intraluminal surface area
• The stomach has rugae and the
liningapproximatesthat of a pouch with a thick mucous
layer
• The mucosa of small intestine is uniquely adapted for
absorption ( folds of Kerckring, villi and microvilli
combine to increase the surface area.
56. Transport of drug from GI tract
Gastric Emptying
• Accomplished by contraction of the antrum of the stomach.
• Ingesting a tablet or small volume of liquid may result in gastric
retention of the drug for 1 hour or longer. After eating a meal,
sustained antral
and pyloric contractions help break up the ingested food and
permit the extrusion of liquid into the duodenum while retaining
particles more than 1mm in diameter within the stomach.
• A mixed meal of solids and liquids usually begins to enter
duodenum in about 30 minutes and requires about 4 hours to
leave.
57. Transport of drug from GI tract
Gastric Emptying
• A major variable in delaying gastric emptying is the
presence of FAT. It promotes absorption of high lipid
soluble drugs
• Most oral medications should be taken in the
absence of food but with full glass of water (except for
drugs that might cause gastric irritation)
58. Transport of drug from GI tract
Influence of Dosage forms
• Most drugs intended for oral use are marketed
in the form of capsules or solid tablets.
• Dissolution process is the disintegration of the
tablet (or the capsules or granules) to yield the
primary drug particles.
• No dissolution process in Liquid dosage forms
59. Transport of drug from GI tract
Influence of Dosage forms
• Various excipients are usually included in solid drug
preparations to promote disintegration and particle
dispersion.
• If disintegration is impaired, drug absorption is
depressed.
• Decreasing the particle size of 85% with a
compensating increase in particle number doubles the
rate of dissolution
60. Transport of drug from GI tract
Influence of Dosage forms
• Some drugs are unstable at low pH (erythromycin) and
others are irritating to the gastric mucosa(ammonium
chloride)
• Enteric coat is consists of a film of shellac or polymeric
substitute to prevent the release of the drug particle in
the stomach.
61. Transport of drug from GI tract
Influence of Dosage forms
• Sustained-release preparations are designed to release a
steady amount of drug within the GIT for 12 to 24 hours.
• Sustained release may be accomplished by using porous
matrix, with the drug located in the interior spaces and on
the external surface.
69. BIOAVAILABILITY
Area Under Curve (AUC)
• Plot of plasma concentration of the drug versus time
• Reflects extent of drug absorption
• Bigger AUC, the greater exposure to drug
70. BIOAVAILABILITY
2 Types Bioavailability
• Absolute
– a certain drug that is administered
through IV
- varies from 0 to 1
• Relative
-a comparison between 2 routes other than IV
- always expressed as % or fraction
71. DISTRIBUTION
• Refers to the movement of drugs throughout the body.
• Process by which a drug reversibly leaves the bloodstream
and enters the interstitium and/or cells of the tissues
74. Capillary Permeability
• After a drug gains access to the systemic circulation, it
becomes diluted by the plasma volume of the entire vascular
compartment.
• The transfer of drugs out of the bloodstream is governed by
the same factors that control its entrance.
• Drug structure
• Hydrophobic drugs
• Hydrophilic drugs
75. Capillary Permeability
Capillary structure
• varies in terms of the fraction of the basement
membrane that isexposed by slit/ tight junctions
between endothelial cells
- ex: brain vs liver & spleen
* blood-brain barrier
76. Volume of Distribution
This is the apparent volume that contains the
amount of drug at a given homogeneous
concentration. It may exceed physiologic
volume (42L)
• The Vd is determined for every drug. This
reflects the extent to which the drug is present
and not in the plasma
77. The human body is composed of different compartments.
As the drug enters the blood stream after absorption, it
enters the various compartments of the
body:
● Plasma Compartment
• Interstitial fluid
• Intracellular fluid
• Total body water
78. Plasma Compartment
• The plasma is the liquid component of blood.
It is approximately 3L in a 70kg individual.
Drugs that are present in the plasma are likely
to be bound to plasma proteins. Drugs with
high molecular weight are likely trapped in the
plasma/intravascular space (e.g. Heparin)
79. Interstitial Fluid
• For a drug that has a low molecular weight, it can
move through the endothelial slits of the blood
vessels
into the interstitial fluid. The average 70kg human
body is assumed to comprised of 11L of interstitial
fluid.
80. Intracellular fluid
• The body is composed of approximately
75 trillion cells, About 28L of fluid is found
intracellularly
Total Body water
• Is composed of approximately 60% of the total
body volume. In a 70kg adult, it is approximated to
be 42L
81. Plasma Protein Binding
• Drugs are transported bound to nonspecific
sites on plasma proteins
• Albumin is a major carrier for acidic drugs
(phenytoin, salicylates)
• Alpha 1-acid glycoprotein binds basic drugs
(quinidine, lidocaine and propanolol)
82. Tissue Binding and Storage
• Drugs capable of associating with plasma proteins are
also likely to bind to tissue constituents. Such binding
does not impede the movement of drugs out of the
bloodstream, but it does slow the rate of elimination
• Fat or adipose tissue is a stable reservoir for lipid soluble
drugs because it has a relatively low blood flow.
• Some drugs are stored in mineralized tissues like bones
and teeth.( F, Lead and Ca chelators such as Tetracycline
may be deposited in during mineralization)
83. METABOLISM
• alternative process that can lead to termination or
alteration of biologic activity
• Conversion of drugs into more hydrophillic
metabolites in preparation for
elimination
• Also known as Biotransformation
84. Drug metabolism or biotransformation reactions
are classified as either:
• Phase 1 (functionalization/redox reactions)
• Phase 2 (biosynthetic/ conjugation reactions)
85. Phase 1
• Makes the drug more polar/ionized (water soluble) by
unmasking a functional group
• Reactions include: hydroxylation, reduction and
oxidation
Enzyme involved:
• NADPH-CYTOCHROME P450 REDUCTASE
• CYTOCHROME P450 (terminal oxidase)
• Found in the smooth endoplasmic reticulum of the liver
• CYP3A4 accounts for the metabolism of over 50% of the
86. • Phase 2
-coupling or conjugation reactions with an
endogenous substance to yield drug conjugates
- conjugation: acetylation, methylation,
glucuronidation, glutathione conjugation, glycine
conjugation, sulfation, water conjugation
87. Toxic Products
• Several compounds have been shown to be
metabolically transformed to reactivate
intermediates that are toxic to various organs
88. >CYP3A is the MOST IMPORTANT as far as drug metabolism
is
concerned. Responsible for the metabolism of the largest
number of drugs, followed by CYP2D6
>CYP2D6 -Present in LARGE amounts in the liver
>CYP2D6 is responsible for the metabolism of a large
fraction of drugs
(about 25%)present in SMALL AMOUNTS in the liver (only 2-
5% of the total content of P450)
>There is a high probability of drug-drug interaction
because CYP3A metabolizes the largest fraction of drugs
89. Excretion
• Removal of drug from the body
• Most important route is through the
kidney into the urine
• Other routes: bile, intestine, lung, or
milk in nursing mothers
90. Three distinct processes that affect
renal elimination of drugs
• Glomerular Filtration
• Active Tubular Secretion
• Passive Tubular reabsorption
91. ELIMINATION is observed to follow either two
patterns:
Linear Kinetics/ First Order Kinetics
• A constant fraction of the drug concentration is
removed per unit time
• Most drugs follow linear kinetics
92. Non-Linear Kinetics/ Zero Order
kinetics
• A constant amount of the drug
concentration is removed per unit time.
• Only several drugs follow non-linear
kinetics: Theophylline, Aspirin, Phenytoin
and Ethanol
93. CLEARANCE
• Measure of the ability of the body to eliminate the drug
2 Major sites of drug elimination
• Kidney
• Renal Clearance (unchanged drug in urine)
Liver
• Biotransformation of parent drug to one or more
metabolites
• Unchanged drug into bile
94. HALF-LIFE (t 1/2)
• Time required to reduce the amount of drug in
the body by one half. This is represented in hours
• Half-life is useful because it indicates the time
required to attain 50% of steady state—or to decay
50% from steady-state conditions—after a change
in the rate of drug administration.
