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Principles of Pharmacology: Part 2

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Principles of Pharmacology: Part 2. Lecture 9. Principles of Drug Action: ... fast increase in blood concentration ---- vomiting. dopaminergic neurons ... – PowerPoint PPT presentation

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Title: 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
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