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