Pharmacology: Studying the principles of Drug Action
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Pharmacokinetics
Pharmacodynamics: Drug action
Two ways to measure drug effects:
Psychopharmacology and
Neuropharmacology

Pharmacokinetics
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I. Administration
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II. Absorption & distribution
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III. Binding and bioavailability
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IV. Inactivation/Biotransformation (metabolization)
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V. Elimination/excretion

I. Administration
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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
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1. Oral
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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
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2. Parenteral (Injection)
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 a. Intravenous b. Intramuscular c. Subcutaneous d. Intracranial e. Epidural f. Intraperitoneal

B. Administration methods, continued
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3. Respiratory
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 a. Inhalation v. intranasal (snorting) b. Smoke (Solids in air suspension) c. Volatile gases
4. Transcutaneous or transdermal
5. Orifice membranes
 a. Sublingual
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b. Rectal: Suppositories or enemas
c. Vaginal: pessaries or douches (1860) d. Other orifices: bougies
6. Topical

Pharmacokinetics
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I. Administration
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II. Absorption & distribution
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Bioavailability
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III. Binding
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IV. Inactivation/biotransformation (metabolization)
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V. Elimination/excretion

II. A. Absorption
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1. Absorption Principles
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2. Absorption Barriers
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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
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Barriers to absorption include
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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)

Absorption Barriers
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To review, barriers to absorption include
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Mucous layers
Membrane pores
Cell walls
First pass metabolism
Placenta
Blood proteins
Fat isolation
Blood-brain barrier

3. Absorption Mechanics
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For each drug, water and fat solubility vary.
Relative solubilities depend on
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 i. pH of the drug ii. pH of the solution iii. pKa of the drug
Solubility percentages depend on ionization ratios

Determining the pKa of a drug
Solution pH: 0 1 2 3 4 5 6 7
Solution pH:
8 9 10 11 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
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 pH of solution

Relative solubilities
Drug pH :
Solution pH:
< 7 (Acid) > 7 (Base)
< 7 (Acid) Un-ionized,
Fat soluble
Ionized,
Water soluble
> 7 (Base) Ionized,
Water soluble
Un-ionized,
Fat soluble

Computing Ionization Ratios
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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 10 X / 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 10 X / 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 = 10 2 /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 = 10 0 = 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 = 10 3 /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 = 10 7 /1=
10,000,000/1. Caffeine is a 600 pound gorilla.

2b. Distribution
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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
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Blood circulation: The crucial minute
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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
Resultant
Elimination
Distribution
2 4 6 8 10 12 14
Time in hours

Pharmacokinetics
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1. Administration
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2. Absorption and distribution
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3. Binding and bioavailability
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4. Inactivation/biotransformation
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5. Elimination/excretion

Pharmacokinetics
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1. Administration
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2. Absorption
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3. Distribution and bioavailability
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4. Biotransformation and elimination

4. Elimination
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Routes of elimination: All body secretions
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Air
Perspiration, saliva, milk
Bile
Urine
Regurgitation
Kidney action
Liver enzyme activity: Generalized

Enzyme activity
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Enzymes in gi tract cells
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Buspirone and grapefruit juice
Enzymes in hepatocytes
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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
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Elimination half-life and side effects
Tolerance and Mithradatism
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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
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Tachyphylaxis
Acute tolerance: The BAC curve
Mixed tolerance
Reverse tolerance or sensitization and potentiation: Fluvoxamine and clozapine; Zantac or Tagamet and alcohol

Balancing distribution and elimination
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Elimination half-life and hangovers
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Accumulation dosing: The 6 half-life rule and regular dosing
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Steady-state dosing
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Therapeutic drug monitoring (TDM)

Accumulation dosing
A 1 B 2 C 3 D 4 E 5 F 6 G 7
Letters = doses; numbers = half-lives

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

Automatic enemas

Nineteenth century inhaler