2. Principles of Drug Action
Drugs modify existing functions within the body; they
do not create function.
No drug has a single action.
Drug effects are determined by the drug’s interaction
with the body.
3.
4. Pharmaceutical Equivalents
FDA definition :
Drugs that contain the same active ingredient
Contain the same active ingredients
Same dosage form
Same route of administration
Identical in strength or concentration
5. Pharmaceutical Alternatives
Drugs products that:
Contain the same therapeutic moiety, or its precursor,
but not necessarily in the same amount or dosage for or
as the same salt or ester.
Each product meets applicable standard of:
Identity
Strength
Quality and Purity
Potency
Content Uniformity
Dissolution/Disentigration Rates
6. Bioequivalence
The absence of a significant difference in the rate and
extent to which the active ingredient in
pharmaceutical equivalents or alternatives become
available at the site of action.
The drug is administered at the same dose and under
similar conditions.
Important when considering generic formulations and
altered formulations of a parent moeity.
Drugs are considered bioequivalent as long as there is
no significant difference in the degree.
7. Therapeutic Equivalents
Drugs that have the same clinical effect and safety
profile when given to patients under the conditions
indicated by the labeling.
If therapeutic equivalence is not shown, the FDA will
take no position on considering the drug without
further investigation and review.
8. Drug Constituents
Drug is made up of one or more active ingredients and
various additives that act as the vehicle or to maintain
stability of the active ingredient.
They are categorized based on chemical and physical
properties.
The constituents are used to influence certain
properties of the final formulation.
9. Drug Formulations
Drugs are formulated to produce either local or
systemic effects.
Local – c0nfined to one area of the body.
Antiseptics, Anti-inflammatories, Local Anesthetics
Systemic – drug is absorbed and delivered to body
tissues by way of the circulatory system.
Antibiotics, Anti-hypertensives, Analgesics
10. Drugs for Local Use
Can have effects on the skin, mucous membranes, and
respiratory tract.
May be water or oil based.
Water based preparations are readily absorbed.
Oil based preparations are more slowly absorbed.
Oil based drugs are not used in the respiratory tract since oil may be
carried to the alveoli, resulting in lipid pneumonia.
11. Systemic Drugs
Absorbed into the circulation to affect one or more
tissue groups.
Administered:
PO - SL
Topically
Parenterally – IV, SQ, IM, ID
Applied to Mucous Membranes
12.
13.
14. Transport Mechanisms
The majority of drugs cross cell membranes by simple
passive diffusion.
Only non-ionized (uncharged) lipid molecules diffuse
easily.
Movement of drug molecules also occur by
Carrier-mediated diffusion
Active transport
Pinocytosis
Filtration
15. Simple Passive Diffusion
Drugs move from high to low concentration.
Absorption occurs as drugs move from high
concentrations in the original compartment to areas of
lower concentration in another.
Accounts for absorption of most drugs from:
GI tract Circulation Target Cells
16.
17. Carrier Mediated Diffusion
Also known as Facilitated transport
A carrier is needed.
Occurs in harmony with concentration gradients.
High Low Concentration
A driving force is not required
Transportation of
Glucose, Certain Vitamins, Amino Acids and Organic Acids
Example – B12 – Intrinsic Factor Complex in GI tract.
18.
19. Filtration
Small drug molecules move along with fluid through
pores in cell walls.
No passage through the lipid matrix of cell.
Capillary membrane pores act as barriers to only very
large drug molecules.
Water soluble drugs and some electrolytes are absorbed
through tissue pores
20.
21. Pinocytosis
Drug is engulfed and moved across cell membrane.
Cell wall invaginates, forms vacuole.
Vacuole breaks off and moves into the cell.
Fat soluble Vitamins A, D,E,K
22.
23. Active Transport
Moves drug molecules against a concentration
gradient.
Uses metabolic energy – ATP
ATP-Drug Complex forms on cell membrane surface.
Complex carries drug through the membrane, then
dissociates.
The rate of active transport is proportional to the drug
concentration.
When carrier mechanisms are saturated, transfer rates
cannot increase.
24.
25. Molecular Size of Drug
Size of drug molecule affects drug transport.
Urea molecules pass easily through cell membranes.
Smaller, lipid-soluble, non-ionized
Glucose molecules are larger and pass with more effort.
Larger, water-soluble, ionized
Once drug concentrations on both sides of the cell
membrane are equal, drug movement ceases.
26. Factors Affecting Absorption
Bioavailability
Rate and extent to which an active drug or its metabolite
is absorbed and becomes available at site of action.
Ionization
Solubility
Absorbing Surface
Pre-systemic Biotransformation
27. Bioavailability
The percentage of Drug available (absorbed), after one
route of administration that produces a pharmacologic
effect.
Determined by measuring the drug concentration in
plasma and by assessing the magnitude of response.
28. Bioavailability
Chemical instability – affects bioavailability – example:
penicillin G is unstable to the pH of gastric secretions.
Nature of Drug Formulation – bioavailability may be
decreased based on the formulation of the drug
Particle size
Salt form
Crystal polymorphism
Presence of excipients – binders, dispersing agents
29. Ionization
Movement of drug by one or more transport
mechanisms is influenced by:
polarity of the cell membrane
polarity of the drug molecule
Substances of like charge repel each other.
Unlike charges attract each other.
Drugs are usually weak acids or weak bases.
31. Drug Ionization
Non-ionized drug molecules are usually lipid-soluble
and able to cross cell membranes.
Ionized drug molecules are unable to penetrate lipid
cell membranes.
A charge on a drug similar to that of the membrane
will delay absorption.
Both the dissolution and ionization of drugs are
affected by the pH of body solutions.
32. Drug Ionization
The ratio of non-ionized drug to an ionized drug is
related to two factors:
The pH of the aqueous medium in which it is dissolved.
The pKa value – Ionization Constant
The pH of of an environment in which exactly half of the drug
molecules are charged and the other half is uncharged.
33. Ionization of Aspirin
Aspirin – weak acid
pKa value of 3.5
pH of solution in which the aspirin is dissolved is
greater than 3.5 – ionized – relatively insoluble in lipid
environments.
pH of solution is less than 3.5, almost entirely non-
ionized – lipid soluble.
34. Ionization of Drugs
Ion Trapping
pH dependent
Drug molecules accumulate on pH favorable side of cell
membrane.
Example – acid drug/acid environment
Aspirin – non-ionized in the stomach.
Crosses cell membranes into plasma – pH 7.4 – ionized and
lipid insoluble -Trapped in plasma
Used therapeutically in drug overdose and poisoning
35. Ion Trapping
Alkalinizing urine promotes ionization of an acid drug
such as Phenobarbitol pKa of 7.4
Elimination is facilitated by trapping it in the urine.
36. Basic Drug Ionization
Basic drugs act opposite from acidic drugs.
Accumulate in a more acidic environment when a pH
difference exists.
A weak organic base – codeine
Placed in stomach – acid environment - ionized
Not lipid soluble – not absorbed
Any drug can be absorbed to some extent in the stomach
and intestines.
37. Solubility
Ability of the drug to dissolve and form a solution.
Must be similar to polar characteristics of the
absorption site (electrical charges).
Lipid soluble cross lipid cell membranes more rapidly.
Drug must be largely hydrophobic yet have solubility
in aqueous solution to be readily absorbed.
38. Absorbing Surface
Blood flow – areas of rich circulation promote
absorption – stomach vs. intestine.
Total Surface Area – intestinal absorption is most
efficient with villi and micro-villi increasing surface
area.
Example: Drugs tend to be absorbed more in the
duodenum, less in the jejunum and least in the ileum
Surface area decreases proximal to distal
Contact Time at Absorption Site – delayed or
enhanced transport.
39. First Pass Hepatic Effect
Drug absorbed across GI tract, must enter portal system
before entering systemic circulation.
This is not true of the mouth or rectum.
If drug is rapidly metabolized by liver, the amount of
unchanged drug that gains access to the systemic
circulation is decreased.
Many drugs, such as propanalol, undergo a significant
biotransformation during a single pass through the portal
system.
Drugs with significant first pass effects require much larger
oral than parenteral doses.
Example: Tricyclic Antidepressants, Analgesics and Anti-
arrhythmics
40.
41.
42. Distribution
Several factors influence drug distribution of an
absorbed drug:
Blood flow
Protein binding
Tissue binding
Solubility
Drugs are distributed through circulation to
Inert plasma and tissue binding sites
Site of action
Organs of elimination
43. Blood Flow
The time required for a drug to be distributed to body
tissues is influenced by:
Cardiac Output
Blood Flow
Well perfused tissues – kidney, heart, liver, brain – faster
uptake.
Poorly perfused tissues – muscle, adipose – slower
uptake.
44. Blood Flow
Drugs leave circulation fluid compartment – cross
capillary membrane – site of action.
Drug concentrations equalize between organs
dependent on blood flow to the area.
IV Barbiturate for anesthesia – pt. will awaken within
minutes – half life is several hours.
Rapid awkening due to decline of drug levels in the
brain – drug redistributed to adipose tissue.
Redistribution rather than elimination that terminates
anesthetic effect.
45. Protein Binding
Once absorbed, drugs are bound to various tissues in
the body.
Only free unbound drug is available to cross cell
membranes to site of action.
The release of a drug from protein binding site occurs
due to falling drug concentration.
Release doesn’t always increase drug action.
46. Protein Binding
Bound drugs are pharmacologically inactive .
Bound drugs cannot be bio-transformed or excreted.
2 Exceptions
High-hepatic Clearance Drugs
Drugs Eliminated by Renal Tubular Secretion
47. Protein Binding Sites
Alpha-1-acid
Albumin
Glyocoproteins
Basic Drugs The most abundant plasma
Quinidine protein
Meperidine Acid Drugs
Imipramine Warfarin
Dipyridamole Penicillin
Chlorpomazine Sulfonamides
48.
49. Protein Binding
A number of disease states alter the concentration of
plasma proteins which affects distribution.
Hypoalbuminemia – low serum protein – drug toxicity
The stronger the bond, the longer the duration of drug
action.
As drug molecules are released from their bonds, they
become free acting.
If two drugs are given – the one with stronger protein
binding or higher concentration will bind more
readily.
50. Drug-Protein Binding
Expressed as a percentage, 0-100%.
Percentage of binding in circulation depends largely on
chemical nature of the drug.
Acetaminophen - ~0% protein bound
Short duration of action
More drug reaches site of action
TID-QID administration
Wafarin – 99% protein bound – 1% pharmacologically
active.
Long duration of action
Once daily administration
52. Barriers to Distribution
Placental Membranes
Non-ionized, lipid soluble drugs readily reach fetus
through maternal circulation.
Placenta is not a barrier to drugs as once thought.
Fetus is exposed to same drug concentrations as those in
the mother, possibly higher.
53. Barriers to Distribution
Blood Brain Barrier - BBB
Highly ionized and protein bound drugs cannot enter
CNS
Drugs that are lipid soluble and poorly bound to plasma
proteins can cross BBB and produce effects in the CNS.
BBB has active transport system pumps drug molecules
out of the brain that may have entered by diffusion.
Important to consider in infection – antimicrobials must
be able to cross BBB.
Meningitis – active transport fails – large amounts of
PCN are allowed to remain in the brain.
54. Blood-Brain Barrier
Brain capillaries are covered by glial cells
(astrocytes)
Assist in forming tight junctions
Endothelial cells form tight junctions
Limits the size and type of molecules that can enter
the brain
55.
56.
57. Dilaudid
What is the dose of oral Dilaudid?
What is the dose of Dilaudid IV?
Why the difference?
58. Volume of Distribution
An estimate of the concentration of drug in the plasma
or blood.
Vd
Vd = the amount of drug administered
plasma drug concentration
(one hour after administration)
The amound of fluid necessary to contain the entire
drug in the body in the same concentration as in the
blood.
59. Vd
Lipid soluble drugs, the Vd is greater than the entire
body fluid volume (over 0.6 L/kg).
Drugs with extensive tissue binding can have a greater
Vd than total body volume (over 1 l/kg).
Vd is influenced by:
Age
Gender – sex body mass differences, pregnancy
Extent of protein binding
Solubility
60. Volume of Distribution
and Body Fluids
Total
Body Interstitial Fluids Total
(21%)
Weight Body
Plasma (4%)
100% Water
Intracellular Fluids
(35%) 60%
61. Fig. Body Fluid Distribution (in the normal 70 kg adult male)
proteins Total Body Water (42 L)
lipids ICV (28 L) ECV (14 L)
Intracellular Volume Extracellular
carbohydrates Volume
Blood Volume (5L)
membranes RBC Plasma
nuclei Volume Volume IFV
microtubules (2L) (3L) (11 L)
mitochondria
Interstitial Fluid
actin
Volume
etc.
IFV = ECV – PV
40% Total Body Water = 60% of body weight
ICV = 40% ECV = 20%
PV = 4%
IFV = 16%
62. % of Body Water
Compartment Infant Adult
Total Body Water 73% 60%
ICF 33% 40%
ECF 40% 20%
63. Case
70 kg male given 500mcg of IV digoxin.
Vd in liters = amount of drug adminstered in mcg
Plasma drug concentration in mg/L
645L = 500mcg digoxin
0.775 mg/L
Pt has 9 times total body fluid volume of a
healthy 70 kg male
64. Vd
Vd
Pool of body fluids that is required to evenly distribute
the drug to all portions of the body.
Does not represent a real volume
Example – Digoxin
Hydrophobic
Distributes rapidly to muscle and adipose
Very small amount is in the plasma
65. Vd
High lipid solubility & High tissue binding
Large Vd and lower drug levels
Less frequent dosing
High water solubility & Highplasma protein binding
Small Vd and high blood levels
More frequent dosing
66. Examples of apparent Vd’s for some drugs
Drug L/Kg L/70 kg
Sulfisoxazole 0.16 11.2
Phenytoin 0.63 44.1
Phenobarbital 0.55 38.5
Diazepam 2.4 168
Digoxin 7 490
