Pharmacology: Studying the principles of Drug Action

1
Pharmacology Studying the principles of Drug
Action

• Pharmacokinetics
• Pharmacodynamics Drug action
• Two ways to measure drug effects
  Psychopharmacology and Neuropharmacology

2
Pharmacokinetics

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

3
I. Administration

• A. Dose or dosage
• Calculation Take the desired or prescribed dose
  (typically in mg/kg) and multiply by the persons
  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.

4
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

5
B. More administration methods

• 2. Parenteral (Injection)
• a. Intravenous
• b. Intramuscular
• c. Subcutaneous
• d. Intracranial
• e. Epidural
• f. Intraperitoneal

6
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

7
Pharmacokinetics

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

8
II. A. Absorption

• 1. Absorption Principles
• 2. Absorption Barriers
• 3. Absorption mechanics

9
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

10
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

11
The blood-brain barrier
Glial feet
Basement membrane (Pia mater)
12
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

13
3. Absorption Mechanics

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

14
Determining the pKa of a drug
1
0
2
4
3
5
6
7
Solution pH
Solution pH
8
9
10
11 12 13 14
15
Determining the pKa of a drug
Ionized
2
8
16
26
38
50
62
74
1
0
2
4
3
5
6
7
Solution pH
Ionized 84 92 98 99
99 99 99
Solution pH
8
9
10
11 12 13 14
16
Ionization for Darnital
17
Relative solubilities
18
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

19
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

20
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.

21
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.

22
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.

23
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.

24
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.

25
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?

26
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

27
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.

28
Half-life curves
Blood level
2 4 6 8 10 12 14
Time in hours
29
Pharmacokinetics

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

30
Pharmacokinetics

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

31
4. Elimination

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

32
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

33
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

34
Tolerance

• More tolerance phenomena
• Tachyphylaxis
• Acute tolerance The BAC curve
• Mixed tolerance
• Reverse tolerance or sensitization and
  potentiation Fluvoxamine and clozapine Zantac
  or Tagamet and alcohol

35
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)

36
Accumulation dosing
Plasma level, mg/dl
50 100 150 200 250 300 350
A 1 B 2 C 3 D 4 E 5 F 6 G
7 Letters doses numbers half-lives
37
Dependence and Addiction

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

38
Automatic enemas
39
Nineteenth century inhaler