Principles of Pharmacology: Part 2

1
Principles of Pharmacology Part 2

• Lecture 9

Principles of Drug Action Absorption,
Distribution Fate Drug Effects and Dose
2
Absorption

• Complete when...
• concentration at target equals
• site of administration
• Controlled by membranes
• capillary walls
• cell
• blood-brain barrier
• placental barrier

3
Capillaries

• Exchange of materials
• b/n blood and cells
• Capillary walls one cell thick
• Pores
• materials can move in/out

4
Movement Across Membrane

• Passive diffusion
• Carrier assisted transport
• diffuse thru gated channels
• Active transport
• requires energy

5
Active Transport

• Metabolic pumps
• require energy
• Membrane proteins
• Pump materials across membrane

6
Blood-Brain Barrier (BBB)

• Barrier b/n circulatory system brain
• Capillaries
• cells in wall tightly packed
• astrocytes
• wrap around capillaries
• tight seal

7
BBB Development

• Incomplete at birth
• up to 2 yrs old
• vulnerable during pregnancy
• Weakening of BBB
• trauma
• infection

8
Chemical Trigger Zone (CTZ)

• Also called Area Postrema
• BBB weaker
• Substances can enter brain
• safety mechanism
• neurons monitor blood
• fast increase in blood concentration ----gt
  vomiting
• dopaminergic neurons

9
Placental Membrane

• Exchange nutrients wastes w/ mother
• Less selective than BBB
• all lipid soluble substances
• Fetus is vulnerable
• incomplete BBB
• lack enzymes for metabolism

10
Placental Membrane

• Teratogens
• chemicals that cause birth defects
• alcohol, nicotine, cocaine, etc.
• Smoking ---gt CO
• reduced O2 levels ---gt brain damage

11
Solubility

• Ability to dissolve in a medium
• water-soluble
• lipid-soluble
• easily crosses membranes
• also BBB

12
Solubility Size Configuration

• Molecular size
• small absorbed easily
• Molecular configuration
• 3 dimensional structure
• isomers - mirror images
• l-amphetamine, d-amphetamine
• generally, l- isomer more active

13
Solubility Ionization

• Ionization decreases solubility
• ion charged particle
• Lipid-soluble ---gt little ionization
• Water-soluble ---gt ionizes easily
• requires active transport

14
Solubility Polarization

• Polarity
• positive negative poles
• H2O
• Polar ---gt hydrophylic
• tend to ionize
• will not cross membrane
• Nonpolar ---gt hydrophobic
• crosses membrane easily

15
Water
Ethanol

-
O
C
C
OH
Polar
Nonpolar
16
Solubility pH

• pH scale 0-14
• Drugs in solution can ionize
• H2O ---gt H and OH-
• of H in solution relative to OH-
• Hi acidic
• Low basic (alkaline)

17
Water 7.0 neutral
pH Scale
7.0
0
14
GI 1.2
Blood 7.4
18
Ion Trapping

• Drug pH important
• Ionization decreases solubility
• acidic drug in alkaline ionize
• alkaline drug in acidic ionize
• Per Os ?
• acidic drug best

19
Redistibution

• Dynamic equilibrium maintained
• Example acidic drug in blood
• 40 ionized to 60 un-ionized
• drug is metabolized
• some ionized ---gt un-ionized
• ratio ionized to un-ionized retained
• 46

20
Best Absorption

• Lipid soluble
• Small
• Nonpolar
• Un-ionized
• pH

21
Depot Binding

• Drug disperses throughout system
• Accumulates in organs tissues
• does not reach target
• silent receptors
• Fat, muscle, organs, bones, etc.

22
Depot Binding

• Unable to cross membranes
• Slow drug fx
• or prevent
• Prolong drug fx
• not metabolized redistribution
• Termination of drug fx

23
Protein Binding

• Large blood proteins
• albumin
• Nonselective binding
• multiple drugs ---gt compete
• higher effective dose for 1
• Valium 99 bound, 1 free
• Redistribution

24
Drug Fate

• Immediate long-term drug disposal
• Determines duration of drug fx
• drug in system---gt drug fx
• Terminates drug fx

25
Half-life

• After complete absorption
• Plasma half-life
• time blood levels drop by half
• distribution half-life
• elimination half-life
• metabolism excretion

26
Biotransformation

• Metabolism
• structure altered ---gt metabolite
• By enzymes
• site of action
• blood plasma
• liver
• Inactivation
• Active metabolites
• e.g., valium, codeine

27
Liver

• Main site of metabolism
• nutrients
• detoxification
• 1st pass metabolism
• GI tract ---gt liver
• Cytochrome P-450
• main enzyme
• enzyme induction
• contributes to tolerance

28
Excretion Kidneys

• Active inactive forms
• Filtration of blood
• Ionization required
• ion-trapping
• Excretion in urine
• Antidiuretic Hormone (ADH)
• regulation of water
• alcohol, caffeine inhibit
• dehydration

29
Excretion Other routes

• Lungs
• alcohol breath
• Breast milk
• acidic ---gt ion traps alkaloids
• alcohol same concentration as blood
• antibiotics
• Also bile, skin, saliva

30
Drug Effects Dose

• Effect of drug depends on dose
• In general...
• as dose increases, fx increase
• to a maximum
• then fx decrease

31
max
Behavior
min
lo
hi
Drug amount (dose)
32
Dose Response

• Drug Effects Variable
• Probability Statements
• Based On Dose response Information
• All or None
• Graded

33
All or None

• of Subjects Affected
• Drug Dose
• Not magnitude

Graded

• Average Response Magnitude
• Drug Dose

34
Drug Response Curve All or None
100
subjects
50
0
0
X
DRUG DOSE
35

• ED50 effective dose in 50 of population

100
subjects
50
ED50
0
0
X
DRUG DOSE
36

• GRADED
• Magnitude info.

B
HI
A
Average Response Magnitude
LO
0
X
DRUG DOSE
37
Potency vs. Efficacy

• Potency
• relative term
• drug A has same effect as drug B...
• but at lower dose
• Maximum efficacy
• maximum response magnitude
• more drug ---gt no effect increase
• but might increase side fx

38
Maximum Efficacy
B
HI
A
Average Response Magnitude
LO
0
X
DRUG DOSE

• B has greater max efficacy than A

39
Potency
B
HI
A
Average Response Magnitude
LO
0
X
DRUG DOSE

• A is more potent than B
• Lower probability of side fx with A

40
Predicting Drug Effects

• Dose Response Curve
• represents mean from groups
• Predict individuals response to drug?
• variability
• standard error of the mean

41
Standard Error
HI
Average Response Magnitude
LO
0
X
DRUG DOSE

• Gives idea of response range
• Prediction represents probability

42

• Comparisons

C
HI
B
A
Average Response Magnitude
LO
0
X
DRUG DOSE
43
Decision Making

• To use or not to use?
• Need information
• Therapeutic Index (safety margin)
• LD50/ED50
• LD lethal dose
• TI 10mg/10mg 1
• 100mg/10mg 10
• 1000mg/10mg 100

44
TI LD50/ ED50
ED
LD
100
subjects
50
0
0
X
DRUG DOSE
45
Side Effects

• ED50 side/ED50 desired
• Side Effects
• Benign
• Untoward

46

• Comparisons of variables
• sex, age, etc.
• or tolerance

A
B
100
subjects
50
0
0
X
DRUG DOSE
47
Tolerance

• After repeated use
• Decreased response to the same dose
• Compensatory responses

48
Types of Tolerance

• Tachyphylaxis
• Drug Disposition Tolerance
• Metabolic
• Pharmacodynamic Tolerance
• NT synthesis Down regulation
• Behavioral Tolerance
• Volitional vs. Associative
• Cross Tolerance

49
Drug Interactions

• Cumulative
• Additive
• Synergistic

50
Cumulative Effects
Hi
Drug B
Response
Drug A
Lo
Time
51
Additive Effects
Hi
A B
Response
A
B
Lo
Time
52
Synergistic Effects
A B
Hi
Response
A
B
Lo
Time
53
Other Sources of Variability

• Nonspecific factors
• Organism
• Psychological
• Environmental
• Task

54
Organism Variables

• Weight
• Interspecies differences
• Intraspecies differences
• Sex Hormonal states
• Age
• Disease
• Nutrition
• Biorhythms
• Physiological state

55
Nonspecific Variables (continued)

• Psychological
• Expectations
• set
• Placebo fx
• Environmental
• Setting
• Task
• Rate dependent fx

56
Rate Dependency

• Interaction of drug
• baseline behavior
• ADHD ritalin
• stimulant to treat hyperactivity?

57
Different Effects, Same Dose

• Why?
• initial activity of system
• Low activity in system
• increases fx
• Hi activity in system
• may decrease fx

58
Low initial activity in system
max
drug dose
x
Behavior
x
min
lo
hi
Drug amount (dose)
59
drug dose
max
x
Behavior
x
min
lo
hi
Drug amount (dose)
High initial activity in system
60
Should you take a drug?

• Rational judgment process
• But often not
• Many factors involved
• Learning
• Classical Operant Conditioning