This document discusses the basic principles of pharmacokinetics, which describes how the body handles drugs over time. It covers the key processes of drug absorption, distribution, metabolism and excretion that determine a drug's levels in tissues. Drug absorption involves passing through cell membranes, which is influenced by a drug's size, lipid solubility, ionization state and other physicochemical properties. The document then discusses the various routes of drug administration and factors affecting absorption through each route. It also introduces concepts like bioavailability and bioequivalence. In distribution, drugs enter the bloodstream and distribute to tissues, with highly perfused organs receiving more drug initially.

1. by Marc Imhotep Cray, M.D.
Basic Medical Sciences Professor
Companion Notes
IVMS BASIC PHARM
General Principles,
Pharmacokinetics and
Pharmacodynamics Notes
Chemotherapy drugs in vials and an IV bottle. (Bill Branson Photographer;
image courtesy of National Cancer Institute Visuals Online.)
1

2. Pharmacokinetics
 “How the body handles a drug over
time.”
 The Time-Dependent Roles of Drug
Absorption, Distribution, and
Elimination (Metabolism/Excretion) in
Determining Drug Levels in Tissues.

3. Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Absorption Free drug Excretion
Bound drug Metabolites
Biotransformation
3

4. Important Properties Affecting
Drug Absorption
• Chemical properties • Physiologic variables
– acid or base – gastric motility
– degree of ionization – pH at the absorption site
– polarity – area of absorbing surface
– molecular weight – blood flow
– lipid solubility or... – presystemic elimination
– partition coefficient – ingestion w/wo food
4

5. Enteral Routes of Drug Administration

6. Oral Ingestion
• Governed by:
– surface area for absorption, blood flow,
physical state of drug, concentration.
– occurs via passive process.
– In theory: weak acids optimally absorbed in
stomach, weak bases in intestine.
– In reality: the overall rate of absorption of
drugs is always greater in the intestine
(surface area, organ function).
6

7. Effect of Changing Rate of Gastric Emptying
• Ingestion of a solid dosage form with a glass of cold
water will accelerate gastric emptying: the
accelerated presentation of the drug to the upper
intestine will significantly increase absorption.
• Ingestion with a fatty meal, acidic drink, or with
another drug with anticholinergic properties, will
retard gastric emptying. Sympathetic output (as in
stress) also slows emptying.
7

8. Sublingual Administration
Absorption from the oral mucosa has
special significance for certain drugs despite
the small surface area.
Nitroglycerin - nonionic, very lipid soluble.
Because of venous drainage into the
superior vena cava, this route “protects” it
from first-pass liver metabolism.
8

9. Rectal Administration
May be useful when oral administration is
precluded by vomiting or when the patient is
unconscious.
Approximately 50% of the drug that is
absorbed from the rectum will bypass the liver,
thus reducing the influence of first-pass
hepatic metabolism.
-irregular and incomplete.
-irritation.
9

10. Parenteral Routes of
Administration

11. Subcutaneous
• Slow and constant absorption.
• Slow-release pellet may be implanted.
• Drug must not be irritating.
11

12. Intramuscular
• Rapid rate of absorption from aqueous
solution, depending on the muscle.
• Perfusion of particular muscle influences
the rate of absorption: gluteus vs. deltoid.
• Slow & constant absorption of drug when
injected in an oil solution or suspension.
12

13. Intraarterial Administration
Occasionally a drug is injected directly into
an artery to localize its effect to a particular
organ, e.g., for liver tumors, head/neck
cancers.
Requires great care and should be reserved
for experts.
13

14. Intrathecal Administration
Necessary route of administration if the
blood-brain barrier and blood-CSF barrier
impede entrance into the CNS.
Injection into the spinal subarachnoid
space: used for local or rapid effects of
drugs on the meninges or cerebrospinal
axis, as in spinal anesthesia or acute CNS
infections.
14

15. Intraperitoneal Administration
• Peritoneal cavity offers a large absorbing
surface area from which drug may enter
the circulation rapidly.
• Seldom used clinically.
• Infection is always a concern.
15

16. Pulmonary Absorption
Inhaled gaseous and volatile drugs are
absorbed by the pulmonary epithelium and
mucous membranes of respiratory tract.
- almost instantaneous absorption
- avoids first-pass metabolism
- local application
16

17. Topical Application
• mucous membranes
Drugs are applied to the mucous membranes
of the conjunctiva, nasopharynx, vagina,
colon, urethra, and bladder for local effects.
Systemic absorption may occur (antidiuretic
hormone via nasal mucosa).
17

18. • Skin
• Few drugs readily penetrate the skin.
• Absorption is proportional to surface area.
• More rapid through abraded, burned or
denuded skin.
• Inflammation increases cutaneous blood
flow and, therefore, absorption.
• Enhanced by suspension in oily vehicle and
rubbing into skin.
18

19. • Eye
- topically applied ophthalmic drugs are
used mainly for their local effects.
-systemic absorption that results from
drainage through the nasolacrimal canal
is usually undesirable; not subject to
first-pass hepatic metabolism.
19

20. Physicochemical Factors In Transfer of
Drugs Across Membranes
• Cell Membranes
• Passive Properties
• Carrier-Mediated Transport
20

21. Fact...
“The absorption, distribution,
biotransformation, and excretion of a drug
all involve its passage across cell
membranes.”
Drugs generally pass through cells rather
than between them. Thus, the plasma
membrane is the common barrier.
Passive diffusion depends on movement
down a concentration gradient.
21

22. 1. Molecular Size
In general, smaller molecules diffuse more
readily across membranes than larger ones
(because the diffusion coefficient is
inversely related to the sq. root of the
MW). This applies to passive diffusion but
NOT to specialized transport mechanisms
(active transport, pinocytosis).
tight junction: MW <200 for diffusion.
large fenestrations in capillaries: MW 20K-30K.
22

23. 2. Lipid-Solubility
Oil:Water Partition Coefficient
The greater the partition coefficient, the
higher the lipid-solubility of the drug, and
the greater its diffusion across membranes.
A non-ionizable compound (or the non-
ionized form of an acid or a base) will reach
an equilibrium across the membrane that is
proportional to its concentration gradient.
23

24. Absorbed from
stomach in 50
580
1 hour
(% of dose) 40
52
30
20
10 1
Other things (MW, pKa) being equal,
absorption of these drugs is 0
barbital secobarbital thiopental
proportional to lipid solubility.
(pKa 7.8) (pKa 7.9) (pKa 7.6)
24

25. 3. Ionization
Most drugs are small (MW < 1000) weak
electrolytes (acids/bases). This influences
passive diffusion since cell membranes are
hydrophobic lipid bilayers that are much
more permeable to the non-ionized forms
of drugs.
The fraction of drug that is non-ionized
depends on its chemical nature, its pKa, and
the local biophase pH...
25

26. You can think of properties this way:
ionized = polar = water-soluble
non-ionized = less polar = more lipid-soluble
_
Think of an acid as having a carboxyl: COOH / COO
Think of a base as having an amino: NH3+ / NH2
*For both acids and bases, pKa = acid dissociation constant,
the pH at which 50% of the molecules are ionized.
Example:
weak acid = aspirin (pKa 3.5)
weak base = morphine (pKa 8.0)
26

27. Weak acid Weak base
H+ extracellular H+
pH
B BH+
HA A-
HA A- B BH+
intracellular
pH
H+ H+
* The pH on each side of the membrane determines
the equilibrium on each side
27

28. A Useful Concept...
Drugs tend to exist in the ionized form when
exposed to their “pH-opposite” chemical
environment.
Acids are increasingly ionized with increasing pH
(basic environment), whereas…
Bases are increasingly ionized with decreasing
pH (acidic environment).
28

29. +
HA acid base HB
pH
cromolyn sodium (2.0) diazepam (3.3)
2
furosemide (3.9) chlordiazepaxide (4.8)
4
sulfamethoxazole (6.0) 6 triamterene (6.1)
phenobarbital (7.4) cimetidine (6.8)
7.4
phenytoin (8.3) morphine (8.0)
8
A
- chlorthalidone (9.4) 10 amantadine (10.1) B
29

30. Henderson-Hasselbalch Eqn.
[protonated]
log = pKa - pH
[unprotonated]
30

31. 31

32. Problem: What percentage of phenobarbital (weak acid, pKa = 7.4)
exists in the ionized form in urine at pH 6.4?
pKa - pH = 7.4 - 6.4 = 1 take antilog of 1 to get the ratio
between non-ionized (HA) and ionized (A-)
antilog of 1 = 10 forms of the drug:
if pH = pKa then HA = A-
if pH < pKa, acid form (HA) will always predominate
if pH > pKa, the basic form (A-) will always predominate
Ratio of HA/A- = 10/1
% ionized = A- / A- + HA X100 = 1 / (1 + 10) X 100 = 9% ionized
32

33. Problem: What percentage of cocaine (weak base, pKa =8 .5)
exists in the non-ionized form in the stomach at pH 2.5?
pKa - pH = 8.5 - 2.5 = 6 take antilog of 6 to get the ratio
between ionized (BH+) and non-ionized
antilog of 6 = 1,000,000 (B) formsof the drug:
if pH = pKa then BH+ = B
if pH < pKa, acid form (BH+) will always predominate
if pH > pKa, the basic form (B) will always predominate
Ratio of BH+/B = 1,000,000/1
% non-ionized = B/ (B + BH+) X100 = 1 X 10-4 % non-ionized
or 0.0001%
33

34. In a Suspected Overdose...
The most appropriate site for sampling to
identify the drug depends on the drug’s
chemical nature.
Acidic drugs concentrate in plasma, whereas the
stomach is a reasonable site for sampling basic
drugs. Diffusion of basic drugs into the stomach
results in almost complete ionization in that low-
pH environment.
34

35. naproxen (weak acid, pKa 5.0)
gastric juice plasma
pH 2.0 pH 7.4
HA = 1.0 HA = 1.0
+ +
A- = 0.001 A- = 251
total total
HA + A- = 1.001 HA + A- = 252
morphine (weak base, pKa 8.0)
small intestine plasma
pH 5.3 pH 7.4
HB+ = 501 HB+ = 4
+ +
B = 1.0 B = 1.0
total total
+ +
HB + B = 502 HB + B = 5
35

36. Other aspects….
• amphetamine (weak base, pKa 10)
– its actions can be prolonged by ingesting
bicarbonate to alkalinize the urine...
– this will increase the fraction of amphetamine in
non-ionized form, which is readily reabsorbed
across the luminal surface of the kidney
nephron...
– in overdose, you may acidify the urine to
increase kidney clearance of amphetamine.
36

37. Certain compounds may exist as strong
electrolytes. This means they are ionized at
all body pH values. They are poorly lipid
soluble.
Ex:
strong acid = glucuronic acid derivatives of
drugs.
strong base = quarternary ammonium
compounds such as acetylcholine.
37

38. Membrane Transfer
passive carrier-mediated endocytosis
diffusion active passive
ATP
ADP-Pi
38

39. Facilitated Diffusion
This is a carrier-mediated process that does
NOT require energy. In this process,
movement of the substance can NOT be
against its concentration gradient.
Necessary for the transport of endogenous
compounds whose rate of movement across
membranes by simple diffusion would be too
slow.
39

40. Active Transport
• Occurrence:
- neuronal membranes, choroid plexus, renal tubule
cells, hepatocytes
• Characteristics
- carrier-mediated
- selectivity
- competitive inhibition by congeners
- *energy requirement
- saturable
- *movement against concentration gradient
*differences from facilitated diffusion
40

41. Endocytosis, Exocytosis,
Internalization
Endocytosis (or pinocytosis): a portion of the
plasma membrane invaginates and then
pinches off from the surface to form an
intracellular vesicle.
Ex: This is the mechanism by which thyroid
follicular cells, in response to TSH, take up
thyroglobulin (MW > 500,000).
41

42. Drug Absorption
Absorption describes the rate and extent at
which a drug leaves its site of administration.
Bioavailability (F) is the extent to which a
drug reaches its site of action, or to a
biological fluid (such as plasma) from which
the drug has access to its site of action.
42

43. Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Absorption Free drug Excretion
Bound drug Metabolites
Biotransformation
43

44. AUC = area under the curve
AUC oral
plasma concentration of drug
Bioavailability = X 100
AUC injected i.v.
AUC
injected I.v.
AUC
oral
time
44

45. Factors Modifying Absorption
• drug solubility (aqueous vs. lipid)
• local conditions (pH)
• local circulation (perfusion)
• surface area
45

46. Bioequivalence
Drugs are pharmaceutical equivalents if they
contain the same active ingredients and are
identical in dose (quantity of drug), dosage form
(e.g., pill formulation), and route of
administration.
Bioequivalence exists between two such
products when the rates and extent of
bioavailability of their active ingredient are not
significantly different.
46

47. Distribution
Once a drug is absorbed into the
bloodstream, it may be distributed into
interstitial and cellular fluids. The actual
pattern of drug distribution reflects
various physiological factors and
physicochemical properties of the drug.
47

48. Phases of Distribution
• first phase
– reflects cardiac output and regional blood
flow. Thus, heart, liver, kidney & brain receive
most of the drug during the first few minutes
after absorption.
• next phase
– delivery to muscle, most viscera, skin and
adipose is slower, and involves a far larger
fraction of the body mass.
48

49. Pharmacokinetics
Locus of Tissue
action reservoirs
“receptors”
Bound Free Bound Free
Systemic
circulation
Absorption Free drug Excretion
Bound drug Metabolites
Biotransformation
49

50. Drug Reservoirs
Body compartments where a drug can
accumulate are reservoirs. They have
dynamic effects on drug availability.
• plasma proteins as reservoirs (bind drug)
• cellular reservoirs
– Adipose (lipophilic drugs)
– Bone (crystal lattice)
– Transcellular (ion trapping)
50

51. Protein Binding
Passive movement of drugs across biological
membranes is influenced by protein
binding. Binding may occur with plasma
proteins or with non-specific tissue proteins
in addition to the drug’s receptors.
***Only drug that is not bound to proteins
(i.e., free or unbound drug) can diffuse
across membranes.
51

52. Plasma Proteins
• albumin
- binds many acidic drugs
• a1-acid glycoprotein for basic drugs
The fraction of total drug in plasma that is bound is
determined by its concentration, its binding affinity,
and the number of binding sites.
At low concentration, binding is a function of Kd; at
high concentration it’s the # of sites.
52

53. Plasma Proteins
• Thyroxine (thyroid hormone T4)
• > 99% bound to plasma proteins.
• The main carrier is the acidic
glycoprotein thyroxine-binding globulin.
• very slowly eliminated from the body,
and has a very long half-life.
53

54. Drugs Binding Primarily to Albumin
barbiturate probenecid
benzodiazepines streptomycin
bilirubin sulfonamides
digotoxin tetracycline
fatty acids tolbutamide
penicillins valproic acid
phenytoin warfarin
phenylbutazone
54

55. Drugs Binding Primarily to
a1-Acid Glycoprotein
alprenolol lidocaine
bupivicaine methadone
desmethylperazine prazosin
dipyridamole propranolol
disopyramide quinidine
etidocaine verapamil
imipramine
55

56. Drugs Binding Primarily to
Lipoproteins
amitriptyline
nortriptyline
56

57. Bone Reservoir
Tetracycline antibiotics (and other divalent
metal ion-chelating agents) and heavy
metals may accumulate in bone. They are
adsorbed onto the bone-crystal surface and
eventually become incorporated into the
crystal lattice.
Bone then can become a reservoir for slow
release of toxic agents (e.g., lead, radium)
into the blood.
57

58. Adipose Reservoir
Many lipid-soluble drugs are stored in fat. In
obesity, fat content may be as high as 50%,
and in starvation it may still be only as low as
10% of body weight.
70% of a thiopental dose may be found in fat 3
hr after administration.
58

59. Thiopental
• A highly lipid-soluble i.v. anesthetic. Blood
flow to the brain is high, so maximal brain
concentrations brain are achieved in minutes
and quickly decline. Plasma levels drop as
diffusion into other tissues (muscle) occurs.
• Onset and termination of anesthesia is rapid.
The third phase represents accumulation in
fat (70% after 3 h). Can store large amounts
and maintain anesthesia.
59

60. Thiopental concentration
(as percent of initial dose)
0
50
100
1
blood
brain
10
minutes
100
muscle
1000
adipose
60

61. GI Tract as Reservoir
Weak bases are passively concentrated in
the stomach from the blood because of the
large pH differential.
Some drugs are excreted in the bile in active
form or as a conjugate that can be
hydrolyzed in the intestine and reabsorbed.
In these cases, and when orally
administered drugs are slowly absorbed, the
GI tract serves as a reservoir.
61

62. Redistribution
Termination of drug action is normally by
biotransformation/excretion, but may
also occur as a result of redistribution
between various compartments.
Particularly true for lipid-soluble drugs
that affect brain and heart.
62

63. Placental Transfer
Drugs cross the placental barrier primarily
by simple passive diffusion. Lipid-soluble,
nonionized drugs readily enter the fetal
bloodstream from maternal circulation.
Rates of drug movement across the
placenta tend to increase towards term as
the tissue layers between maternal blood
and fetal capillaries thin.
63

64. Clinical Pharmacokinetics
Fundamental hypothesis: a relationship exists
between the pharmacological or toxic
response to a drug and the accessible
concentration of the drug (e.g., in blood).
• volume of distribution (Vd)
• clearance (CL)
• bioavailability (F)
64

65. Volume of Distribution
Volume of distribution (Vd) relates the
amount of drug in the body to the plasma
concentration of drug (C).
**The apparent volume of distribution is a
calculated space and does not always
conform to any actual anatomic space.**
Note: Vd is the fluid volume the drug would have to be distributed in if Cp were
representative of the drug concentration throughout the body.
65

66. Total body water
plasma volume
extracellular
plasma
3 liters
interstitial
volume interstitial volume
15 liters
intracellular
volume
intracellular 12 liters
42 liters
27 liters
66

67. At steady-state:
total drug in body (mg)
Vd = ------------------------------
plasma conc. (mg/ml)
67

68. Example of Vd
The plasma volume of a 70-kg man ~ 3L, blood volume ~
5.5L, extracellular fluid volume ~ 12L, and total body
water ~ 42L.
If 500 mg of digoxin were in his body, Cplasma would be ~
0.7 ng/ml. Dividing 500 mg by 0.7 ng/ml yields a Vd of
700L, a value 10 times total body volume! Huh?
Digoxin is hydrophobic and distributes preferentially to
muscle and fat, leaving very little drug in plasma. The
digoxin dose required therapeutically depends on body
composition.
68

69. Clearance (CL)
Clearance is the most important property to
consider when a rational regimen for long-
term drug administration is designed. The
clinician usually wants to maintain steady-
state drug concentrations known to be
within the therapeutic range.
CL = dosing rate / Css
CL = rate of elimination / Css
(volume/time) = (mass of drug/time) / (mass of drug/volume)
69

70. Clearance
Clearance does not indicate how much
drug is removed but, rather, the volume
of blood that would have to be
completely freed of drug to account for
the elimination rate.
CL is expressed as volume per unit time.
70

71. Sum of all process
contributing to dis-
appearance of drug
from plasma
Drug in plasma at Drug concentration
concentration of 2 mg/ml in plasma is less after
each pass through
elimination/metabolism
process
Drug molecules disappearing from
plasma at rate of 400 mg/min
400 mg/min
CL = = 200 ml/min
2 mg/ml
71

72. Example: cephalexin, CLplasma = 4.3 ml/min/kg
• For a 70-kg man, CLp = 300 ml/min, with renal clearance
accounting for 91% of this elimination.
• So, the kidney is able to excrete cephalexin at a rate such
that ~ 273 ml of plasma is cleared of drug per minute. Since
clearance is usually assumed to remain constant in a stable
patient, the total rate of elimination of cephalexin depends
on the concentration of drug in plasma.
72

73. Example: propranolol, CLp = 12 ml/min/kg or 840
ml/min in a 70-kg man.
The drug is cleared almost exclusively by the
liver.
Every minute, the liver is able to remove the
amount of drug contained in 840 ml of
plasma.
73

74. • Clearance of most drugs is constant over a
range of concentrations.
• This means that elimination is not
saturated and its rate is directly
proportional to the drug concentration: this
is a description of 1st-order elimination.
74

75. CL in a given organ may be defined in terms of
blood flow and [drug].
Q = blood flow to organ (volume/min)
CA = arterial drug conc. (mass/volume)
CV = venous drug conc.
rate of elimination = (Q x CA) - (Q x CV) = Q (CA-
CV)
75

76. Source: First Aid for the USMLE Step 1, 2012 pg.259-261
76

77. Source: First Aid for the USMLE Step 1, 2012 pg.259-261
77

78. Source: First Aid for the USMLE Step 1, 2012 pg.259-261
78

79. Source: First Aid for the USMLE Step 1, 2012 pg.259-261
79

80. Source: First Aid for the USMLE Step 1, 2012 pg.259-261
80

81. Source: First Aid for the USMLE Step 1, 2012 pg.259-261
81

82. FOR ADDITIONAL STUDY:
PHARM2000
Medical Pharmacology and Disease-Based Integrated Instruction
Programmed Study: Pharmacology Content, Practice Questions, Practice Exams
Michael Gordon, Ph.D., site developer; email:
Michael Gordon
Chapter 1: General Principles--Introduction
Practice question set #1
Practice question set #2
Practice question set #3
Practice question set #4
Chapter 2: Pharmacokinetics
Practice question set #1
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Practice question set #5
Practice question set #6
Flashcards
Problem set #1
Problem set #2
Practice Exam #1
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Chapter 3: Pharmacodynamics
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