This document discusses principles of drug action and distribution in the body. It defines key terms like pharmaceutical equivalents, alternatives, and bioequivalence. It describes how drugs are absorbed and distributed, factors that influence absorption like ionization and protein binding, and transport mechanisms. The volume of distribution is discussed as well as barriers to drug distribution like the blood brain barrier.

1. University of Miami
Advanced Practice Preparation

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.

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

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

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.

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

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

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.

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.

30. Ionization of Drugs
 Positively Charged  Negatively Charged
 Alkaloids  Acids
 Bases  Acid Radicals
 Metallic Radicals

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

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

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

51. Solubility
 Lipid soluble drugs distributed rapidly.
 Lipid insoluble drugs distributed slowly.

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

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

67. Post-Test