Pharmacology: Studying the

principles of Drug Action

Pharmacokinetics
Pharmacodynamics: Drug action
Two ways to measure drug effects:

Psychopharmacologylook at changes
in mood, cognition, and action after
taking a drug
Neuropharmacologyexamine changes
in the way cells function after exposure
to a drug

Pharmacokinetics

I. Administration

II. Absorption & distribution

III. Binding and bioavailability

IV. Inactivation/Biotransformation (metabolization)

V. Elimination/excretion

I. Administration

A. Dose or dosage
Calculation: Take the desired or
prescribed dose (typically in mg/kg) and
multiply by the persons mass (in kg).
Thus, for example,
0.10mg/kg x 60kg = 6 mg dose
Dosage may also be measured in mg/dl
of blood plasma, but that is after
administration and absorption.

B. Administration methods

1. Oral
Advantages and disadvantages
Formulations:

Elixirs and syrups

Tablets, capsules, and pills

Historic formulations:
Powder (Take a powder)
Cachets
Lozenges and pastilles

B. More administration
methods

2. Parenteral (Injection)
a. Intravenous
b. Intramuscular
c. Subcutaneous
d. Intracranial or intracerebroventricular
e. Epidural
f. Intraperitoneal

B. Administration methods,
continued

3. Respiratory

4. Transcutaneous or transdermal
5. Orifice membranes

a. Inhalation v. intranasal (snorting)

b. Smoke (Solids in air suspension)
c. Volatile gases

a. Sublingual
b. Rectal: Suppositories or enemas
c. Vaginal: pessaries or douches (1860)
d. Other orifices: bougies

6. Topical

Pharmacokinetics

I. Administration

II. Absorption & distribution

Bioavailability

III. Binding

IV. Inactivation/biotransformation (metabolization)

V. Elimination/excretion

II. A. Absorption

1. Absorption Principles

2. Absorption Barriers

3. Absorption Mechanics

1. Absorption Principles

a. General principle: Diffusion, which depends on

i. Solubility (fat and/or water)

ii. Molecular diameter

iii. Volatility (air)

iv. Affinity (Proteins, water [hydrophilic], oil

b. Absorption is influenced by amount of blood

flow at the site of administration

2. Absorption Barriers

Barriers to absorption include

Mucous layers
Membrane pores
Cell walls
First-pass metabolism
Placenta
Blood proteins
Fat isolation
Blood-brain barrier

Exceptions: Area postrema, median eminence of

hypothalamus

The blood-brain barrier

Glial feet
Basement
membrane
(Pia mater)

2. Absorption Barriers

To review, barriers to absorption include

Mucous layers
Membrane pores
Cell walls
First pass metabolism
Placenta
Blood proteins
Fat isolation
Blood-brain barrier

3. Absorption Mechanics

a. For each drug, water and fat solubility

vary. Some of the molecules of a given
drug are fat soluble while other molecules
of the same drug are water soluble.
b. Relative solubilities (fat soluble % and
water soluble %) depend on

i. pH of the drug
ii. pH of the solution
iii. pKa of the drug

c. Solubility percentages depend on

ionization ratios

Determining the pKa of a

drug

Solution pH: 0

Solution pH:

10

11

12

13

14

Determining the pKa of a

drug
% Ionized

16

26

38

50

62

74

Solution pH: 0

% Ionized

84

92

98

99

99

99

99

Solution pH:

10

11

12

13

14

% Ionization for Darnital

120

% Ionization

100
80
60
40
20
0
0

pH of solution

10 11 12 13 14

Relative solubilities
Solution pH:
Drug pH:

< 7 (Acid)

> 7 (Base)

< 7 (Acid)

Un-ionized,
Fat soluble

Ionized,
Water soluble

> 7 (Base)

Ionized,
Un-ionized,
Water soluble Fat soluble

Computing Ionization Ratios

According to the Henderson-Hasselbalch

equation, the difference between the pH
of the solution and the pKa of the drug is
the common logarithm of the ratio of
ionized to unionized forms of the drug.
For acid drugs
log(ionized/unionized) = pH - pKa, or
ratio of ionized to unionized is 10X / 1, where
X = pH pKa

Computing ionization ratios,

2
For basic drugs, everything is the
same except that the ratio reverses:
Log(unionized/ionized) = pH pKa, or
Ratio of unionized to ionized is 10X /
1, where
X = pH pKa

Examples
Darnital, a weak acid, has a pKa of 5.5.
Taken orally, it is in a stomach solution of
pH 3.5.
pH pKa = 3.5 5.5 = -2
Since Darnital is an acid drug, we use the
alphabetical formula ionized/unionized.
ionized/unionized = 10-2/1= 1/100
For every 1 molecule of Darnital that is
ionized, 100 are unionized. Darnital in
the stomach is highly fat soluble.

But look what happens

The highly fat soluble Darnital readily
crosses the stomach membranes and
enters blood plasma, which has a pH of
7.5
pH pKa = 7.5 5.5 = 2
ionized/unionized = 102/1= 100/1
For every 100 molecules of Darnital that
are ionized, only 1 is unionized. Darnital
in the blood is not very fat soluble.
Darnital will be subject to ion trapping.

Another example
Endital, a weak base with a pKa of 7.5
is dissolved in the stomach, pH 3.5
pH pKa = 3.5 7.5 = -4
Since Endital is a base drug, we use
the ratio backwards:
unionized/ionized.
unionized/ionized = 10-4/1= 1/10,000
In the stomach, Endital will be mostly
ionized, and not very fat soluble.

But
If we inject Endital intravenously into
the blood, with a pH of 7.5,
pH pKa = 7.5 7.5 = 0
unionized/ionized = 100 = 1/1
In the blood, Endital will be equally
ionized and unionized. Half of the
molecules of Endital will be fat
soluble, and will readily leave the
blood and enter the brain.
A dynamic equilibrium follows.

An oddity
Caffeine is a base drug, but it has a pKa of 0.5
pH pKa = 3.5 0.5 = 3
Since caffeine is a base drug, we use the ratio
backwards: unionized/ionized.
unionized/ionized = 103/1= 1000/1
In the stomach, caffeine will be mostly
unionized, and fat soluble!
In the blood, caffeine will be even more
unionized and fat soluble:
pH pKa = 7.5 0.5 = 7, ratio = 107/1=
10,000,000/1. Caffeine is a 600 pound gorilla.

2b. Distribution

The generalized distribution of a drug

throughout the body controls the
movement of a drug by its effect on
ionization ratios
Distribution also controls how long a drug
acts and how intense are its effects
Generalized distribution of a drug
accounts for most of the side effects
produced
Is there a magic bullet?

Mechanisms of distribution

Blood circulation: The crucial minute

But blood flow is greater to crucial organs

than to muscle, skin, or bone.

Blood circulation is the main factor affecting

bioavailability.

Lymphatic circulation

Depot binding

CSF circulation: The ventricular system

Distribution half-life and

therapeutic levels
Distribution half-life: the amount of time
it takes for half of the drug to be
distributed throughout the body
Therapeutic level: the minimum amount
of the distributed drug necessary for
the main effect.

Half-life curves

Blood level

Resultant

Elimination
Distribution
2

6 8 10 12
Time in hours

14

Pharmacokinetics

1. Administration

2. Absorption and distribution

3. Binding and bioavailability

4. Inactivation/biotransformation

5. Elimination/excretion

Pharmacokinetics

1. Administration

2. Absorption

3. Distribution and bioavailability

4. Biotransformation and
elimination

4. Elimination

Routes of elimination: All body

secretions
Air
Perspiration, saliva, milk
Bile
Urine
Regurgitation

Kidney action
Liver enzyme activity: Generalized

Enzyme activity

Enzymes in gi tract cells

Buspirone and grapefruit juice

Enzymes in hepatocytes

Cytochrome P-450 families: CYP1-3

Cross-tolerance

Biotransformation
Type I and type II
Metabolites are larger, less fat soluble, more water
soluble
Metabolite activity is usually lowered

Elimination phenomena
Elimination half-life and side effects
Tolerance and Mithradatism

Metabolic tolerance or enzymeinduction tolerance

Cross-tolerance: Carbamazepine and
fluoxetine (Tegretol and Prozac)
Cellular-adaptive tolerance
Behavioral conditioning and statedependent tolerance

Tolerance
More tolerance phenomena
Tachyphylaxis
Acute tolerance: The BAC curve
Mixed tolerance
Reverse tolerance or sensitization and
potentiation: Fluvoxamine (Luvox)
and clozapine (Clozaril); Zantac or
Tagamet and alcohol

Balancing distribution and

elimination

Elimination half-life and hangovers

Accumulation dosing: The 6 half-life

rule and regular dosing

Steady-state dosing

Therapeutic drug monitoring (TDM)

Accumulation dosing

A 1 B

2 C

3 D 4 E

5 F

Letters = doses; numbers = half-lives

6 G 7

An example: Clozapine
pharmacokinetics

Pharmacokinetics and metabolism

After oral administration the drug is rapidly absorbed. There is extensive first
pass metabolism and only 27-50%of the dose reaches the systemic circulation
unchanged.
Clozapine's plasma concentration has been observed to vary from patient to
patient. Various individual factors may vary response such as smoking, hepatic
metabolism, gastric absorption, age, and possibly gender.

Clozapine is rapidly distributed; it crosses the blood-brain barrier and is

distributed in breast milk. It is
95% bound to plasma proteins. Steady state plasma concentration is reached
after 7-10 days. The onset of anti-psychotic effect can take several weeks, but
maximum effect may require several months. In treatment resistant
schizophrenia, patients have been reported to continue to improve for at least
two years after the start of clozapine treatment.
Clozapine metabolizes into various metabolites, out of which only norclozapine
(desmethyl metabolite) is pharmacologically active. The other metabolites do not
appear to have clinically significant activity.
Its plasma concentration declines in the biphasic manner, typical of oral antipsychotics and its mean
elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in
urine and 30% in the
faeces.

Dependence and Addiction

Physiological dependence: The
abstinence syndrome
Cross-dependence
Habituation and conditioning
Addiction and behavioral
reinforcement

Positive reinforcement
Negative reinforcement

Automatic enemas

Nineteenth century inhaler