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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
a. Inhalation v. intranasal (snorting)
b. Smoke (Solids in air suspension)
c. Volatile gases
4. Transcutaneous or transdermal
5. Orifice membranes
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
Basement
membrane
(Pia mater)
2. Absorption Barriers
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
% Ionization
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH of solution
Relative solubilities
Solution pH:
Resultant
Blood level
Elimination
Distribution
2 4 6 8 10 12 14
Time in hours
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
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
Mixed tolerance
A 1 B 2 C 3 D 4 E 5 F 6 G 7
Letters = doses; numbers = half-lives
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 anti-
psychotics 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