Transcript Principles of Drug Action

Pharmacology: Studying the
principles of Drug Action
Pharmacokinetics
 Pharmacodynamics: Drug action
 Two ways to measure drug effects:

Psychopharmacology—look at changes
in mood, cognition, and action after
taking a drug
 Neuropharmacology—examine 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 person’s 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:
1
8
2
9
3
10
4
11
5
6
7
12
13
14
Determining the pKa of a
drug
% Ionized
2
8
16
26
38
50
62
74
Solution pH: 0
1
2
3
4
5
6
7
% Ionized
84
92
98
99
99
99
99
Solution pH:
8
9
10
11
12
13
14
% Ionization for Darnital
120
% Ionization
100
80
60
40
20
0
0
1
2
3
4
5
6
7
8
pH of solution
9
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
4
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