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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
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
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
Basementmembrane(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
10 2 43 5 6 7
8 9 10 11 12 13 14
Solution pH:
Solution pH:
Determining the pKa of a drug
2 8 16 26 38 50 62 74
10 2 43 5 6 7
8 9 10 11 12 13 14
Solution pH:
Solution pH:
% Ionized
% Ionized 84 92 98 99 99 99 99
% Ionization for Darnital
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH of solution
% I
on
izat
ion
Relative solubilities
Solution pH:
Drug 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
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 drugslog(ionized/unionized) = pH - pKa, orratio of ionized to unionized is 10X / 1, whereX = pH – pKa
Computing ionization ratios, 2
For basic drugs, everything is the same except that the ratio reverses:
Log(unionized/ionized) = pH – pKa, orRatio of unionized to ionized is 10X / 1,
whereX = pH – pKa
ExamplesDarnital, 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 = -2Since 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 = 2ionized/unionized = 102/1= 100/1For 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 = -4Since Endital is a base drug, we use
the ratio backwards: unionized/ionized.
unionized/ionized = 10-4/1= 1/10,000In 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 = 0unionized/ionized = 100 = 1/1In 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 oddityCaffeine is a base drug, but it has a pKa of 0.5pH – pKa = 3.5 – 0.5 = 3Since caffeine is a base drug, we use the ratio
backwards: unionized/ionized.unionized/ionized = 103/1= 1000/1In 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
Time in hours
Blo
od
level
Elimination
Distribution
2 4 6 8 10 12 14
Resultant
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 enzyme-induction tolerance
Cross-tolerance: Carbamazepine and fluoxetine (Tegretol and Prozac)
Cellular-adaptive tolerance Behavioral conditioning and state-
dependent 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 6 G 7Letters = doses; numbers = half-lives
Pla
sma level, m
g/d
l
50
1
00
1
50
2
00
25
0
30
0
35
0
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
Physiological dependence: The abstinence syndrome
Cross-dependence Habituation and conditioning Addiction and behavioral
reinforcement Positive reinforcement Negative reinforcement
Automatic enemas
Nineteenth century inhaler
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