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3. Pharmacokinetics
Pharmacokinetics
•• Time course of drug absorption,
Time course of drug absorption,
distribution, metabolism, excretion
distribution, metabolism, excretion
How the drug
How the drug
comes and goes.
comes and goes.
5. Liberation
Liberation
••
••
Applies to drugs given orally
Applies to drugs given orally
Components
Components
– Release of drug from pill, tablet, capsule
– Release of drug from pill, tablet, capsule
– Dissolving of active drug in GI fluids
– Dissolving of active drug in GI fluids
Ex: Enteric coated
Ex: Enteric coated
aspirin slows absorption in
aspirin slows absorption in
stomach vs non-coated
stomach vs non-coated
9. LaChatlier’s Principle
LaChatlier’s Principle
a.k.a. Mass Action
a.k.a. Mass Action
System
System
at
at
Equilibrium
Equilibrium
4 Na+
+ 4 Cl_
A reaction at equilibrium
A reaction at equilibrium
responds to stress in a
responds to stress in a
way to best return to
way to best return to
equilibrium
equilibrium
4 NaCl
10. 4. System returnsequilibrium
System responds system
4. 3.2. Stress responds to stress
System returnsequilibrium
3.1. Stress applied equilibrium!
2.1. System at to toto stress
System applied equilibrium!
System at to to system
⇑ by 4
8 4
4 Na+
System not at
System not at
An example of
equilibrium!
equilibrium!
LaChatlier’s
Principle
+
4 NaCl
dissociate
8
4 Cl-
⇑
8
⇓ by 4
12NaCl
8
4 NaCl
12. Environmental pH and
Environmental pH and
Ionization
Ionization
If we put an acidic drug in an
If we put an acidic drug in an
environment with a lot of H++ (low pH)
environment with a lot of H (low pH)
what will this equilibrium do?
what will this equilibrium do?
HA
HA
HA
HA
HA
H+ + A -
⇑ System atformenvironment
H++ from formenvironment
Non-ionizedat Equilibrium
⇑ System acid predominates!
H from Equilibrium
Non-ionized acid predominates!
13. A real live, actual clinical
A real live, actual clinical
question...
question...
Aspirin is an acidic drug. In the
Aspirin is an acidic drug. In the
stomach will it exist mostly in ionized
stomach will it exist mostly in ionized
or non-ionized form?
or non-ionized form?
NON-IONIZED
Why?
Why?
14. How will this affect aspirin
How will this affect aspirin
absorption?
absorption?
Lipid Bilayer
Ionized form
Ionized form
(charged)
(charged)
A-
Ionized form
Ionized form
(uncharged)
(uncharged)
HA
HA
15. Moral of the story...
Moral of the story...
Acidic drugs are best absorbed from
Acidic drugs are best absorbed from
acidic environments
acidic environments
Basic drugs are best absorbed from
Basic drugs are best absorbed from
basic environments
basic environments
16. So...
So...
To ⇑ absorption of an acidic drug…
To ⇑ absorption of an acidic drug…
acidify the environment
acidify the environment
To ⇓ absorption of an acidic drug…
To ⇓ absorption of an acidic drug…
alkalanize the environment...
alkalanize the environment...
17. Distribution
Distribution
••
••
••
••
Rate of perfusion
Rate of perfusion
Plasma protein (albumin) binding
Plasma protein (albumin) binding
Accumulation in tissues
Accumulation in tissues
Ability to cross membranes
Ability to cross membranes
– Blood-brain barrier
– Blood-brain barrier
– Placental barrier
– Placental barrier
18. Plasma Protein Binding
Plasma Protein Binding
warfarin (Coumadin) is highly protein
warfarin (Coumadin) is highly protein
bound (99%). Aspirin binds to the same
bound (99%). Aspirin binds to the same
site on serum proteins as does
site on serum proteins as does
Coumadin. If a patient on Coumadin
Coumadin. If a patient on Coumadin
also takes aspirin, what will happen?
also takes aspirin, what will happen?
1) Why?
1) Why?
The available Coumadin will
2) Why do we care?
2) Why do we care?
increase.
19. Blood-Brain Barrier
Blood-Brain Barrier
The blood brain barrier consists of
The blood brain barrier consists of
cell tightly packed around the
cell tightly packed around the
capillaries of the CNS. What
capillaries of the CNS. What
characteristics must a drug possess
characteristics must a drug possess
to easily cross this barrier?
to easily cross this barrier?
Non-protein bound, non-ionized,
Why?
Why? soluble
and highly lipid
20. Metabolism
Metabolism
(Biotransformation)
(Biotransformation)
•• Two effects
Two effects
– Transformation to less active metabolite
– Transformation to less active metabolite
– Enhancement of solubility
– Enhancement of solubility
••
••
Liver = primary site
Liver = primary site
Liver disease
Liver disease
– Slows metabolism
– Slows metabolism
– Prolongs effects
– Prolongs effects
21. Hepatic ‘First-Pass’
Hepatic ‘First-Pass’
Metabolism
Metabolism
••
••
••
••
Affects orally administered drugs
Affects orally administered drugs
Metabolism of drug by liver before drug
Metabolism of drug by liver before drug
reaches systemic circulation
reaches systemic circulation
Drug absorbed into portal circulation, must
Drug absorbed into portal circulation, must
pass through liver to reach systemic
pass through liver to reach systemic
circulation
circulation
May reduce availability of drug
May reduce availability of drug
23. Active Tubular Transport
Active Tubular Transport
Probenecid is moved into the urine by
Probenecid is moved into the urine by
the same transport pump that moves
the same transport pump that moves
many antibiotics. Why is probenecid
many antibiotics. Why is probenecid
sometimes given as an adjunct to
sometimes given as an adjunct to
antibiotic therapy?
antibiotic therapy?
It competes with the
antibiotic at the pump and
slows its excretion.
24. Urine pH and Elimination
Urine pH and Elimination
A patient has overdosed on
A patient has overdosed on
phenobartital. Phenobarbital is an acid.
phenobartital. Phenobarbital is an acid.
If we ‘alkalinalize’ the urine by giving
If we ‘alkalinalize’ the urine by giving
bicarbonate what will happen to the
bicarbonate what will happen to the
phenobarbital molecules as they are
phenobarbital molecules as they are
filtered through the renal tubules?
filtered through the renal tubules?
They will ionize...
25. How will this affect phenobarbital
How will this affect phenobarbital
reabsorption by the kidney?
reabsorption by the kidney?
Non-ionized
HA
Ionized
H+ + A -
Decreased reabsorption
Decreased reabsorption
Increased elimination
Increased elimination
27. Biological Half-life (t 1/2))
Biological Half-life (t 1/2
•• Amount of time to eliminate 1/2 of total
Amount of time to eliminate 1/2 of total
drug amount
drug amount
•• Shorter tt 1/2 may need more frequent doses
Shorter 1/2 may need more frequent doses
•• Hepatic disease may increase tt1/2
Hepatic disease may increase 1/2
28. A drug has a half life of 10 seconds. You
A drug has a half life of 10 seconds. You
give a patient a dose of 6mg. After 30
give a patient a dose of 6mg. After 30
seconds how much of the drug remains?
seconds how much of the drug remains?
Time
Time
Amount
Amount
0 sec
0 sec
6 mg
6 mg
10 sec
10 sec
3 mg
3 mg
20 sec
20 sec
1.5 mg
1.5 mg
30 sec
30 sec
0.75 mg
0.75 mg
29. Administration Routes
Administration Routes
•• Intravenous
Intravenous
– Fastest, Most dangerous
– Fastest, Most dangerous
•• Endotracheal
Endotracheal
– Lidocaine, atropine, narcan, epinephrine
– Lidocaine, atropine, narcan, epinephrine
•• Inhalation
Inhalation
– Bronchodilators via nebulizers
– Bronchodilators via nebulizers
•• Transmucosal
Transmucosal
– Rectal or sublingual
– Rectal or sublingual
30. Administration Routes
Administration Routes
•• Intramuscular
Intramuscular
– Depends on perfusion quality
– Depends on perfusion quality
•• Subcutaneous
Subcutaneous
– Depends on perfusion quality
– Depends on perfusion quality
•• Oral
Oral
– Slow, unpredictable
– Slow, unpredictable
– Little prehospital use
– Little prehospital use
31. Pharmacodynamics
Pharmacodynamics
•• The biochemical and physiologic
The biochemical and physiologic
mechanisms of drug action
mechanisms of drug action
What the drug
What the drug
does when it gets there.
does when it gets there.
40. Non-receptor Mechanisms
Non-receptor Mechanisms
•• Combining With Other Chemicals
Combining With Other Chemicals
– Antacids
– Antacids
– Antiseptic effects of alcohol, phenol
– Antiseptic effects of alcohol, phenol
– Chelation of heavy metals
– Chelation of heavy metals
41. Non-receptor Mechanisms
Non-receptor Mechanisms
•• Anti-metabolites
Anti-metabolites
– Enter biochemical reactions in place of normal
– Enter biochemical reactions in place of normal
substrate “competitors”
substrate “competitors”
– Result in biologically inactive product
– Result in biologically inactive product
– Examples
– Examples
•• Some anti-neoplastics
Some anti-neoplastics
•• Some anti-infectives
Some anti-infectives
45. Dose Response Relationships
Dose Response Relationships
•• Potency
Potency
– Absolute amount of drug required to produce
– Absolute amount of drug required to produce
an effect
an effect
– More potent drug is the one that requires lower
– More potent drug is the one that requires lower
dose to cause same effect
dose to cause same effect
47. Dose Response Relationships
Dose Response Relationships
•• Threshold (minimal) dose
Threshold (minimal) dose
– Least amount needed to produce desired effects
– Least amount needed to produce desired effects
•• Maximum effect
Maximum effect
– Greatest response produced regardless of dose
– Greatest response produced regardless of dose
used
used
49. Dose Response Relationships
Dose Response Relationships
•• Loading dose
Loading dose
– Bolus of drug given initially to rapidly reach
– Bolus of drug given initially to rapidly reach
therapeutic levels
therapeutic levels
•• Maintenance dose
Maintenance dose
– Lower dose of drug given continuously or at
– Lower dose of drug given continuously or at
regular intervals to maintain therapeutic levels
regular intervals to maintain therapeutic levels
50. Therapeutic Index
Therapeutic Index
••
••
••
••
Drug’s safety margin
Drug’s safety margin
Must be >1 for drug to be usable
Must be >1 for drug to be usable
Digitalis has a TI of 2
Digitalis has a TI of 2
Penicillin has TI of >100
Penicillin has TI of >100
LD50
TI =
ED50
51. Therapeutic Index
Therapeutic Index
Why don’t we use a
Why don’t we use a
drug with a TI <1?
drug with a TI <1?
ED50 < LD50 = Very Bad!
ED50 < LD50 = Very Bad!
52. Factors Altering Drug
Factors Altering Drug
Responses
Responses
•• Age
Age
– Pediatric or geriatric
– Pediatric or geriatric
– Immature or decreased hepatic, renal function
– Immature or decreased hepatic, renal function
•• Weight
Weight
– Big patients “spread” drug over larger volume
– Big patients “spread” drug over larger volume
•• Gender
Gender
– Difference in sizes
– Difference in sizes
– Difference in fat/water distribution
– Difference in fat/water distribution
53. Factors Altering Drug
Factors Altering Drug
Responses
Responses
•• Environment
Environment
– Heat or cold
– Heat or cold
– Presence or real or perceived threats
– Presence or real or perceived threats
••
••
Fever
Fever
Shock
Shock
54. Factors Altering Drug
Factors Altering Drug
Responses
Responses
•• Pathology
Pathology
– Drug may aggravate underlying pathology
– Drug may aggravate underlying pathology
– Hepatic disease may slow drug metabolism
– Hepatic disease may slow drug metabolism
– Renal disease may slow drug elimination
– Renal disease may slow drug elimination
– Acid/base abnormalities may change drug
– Acid/base abnormalities may change drug
absorption or elimination
absorption or elimination
55. Influencing factors
Influencing factors
•• Genetic effects
Genetic effects
– Lack of specific enzymes
– Lack of specific enzymes
– Lower metabolic rate
– Lower metabolic rate
•• Psychological factors
Psychological factors
– Placebo effect
– Placebo effect
56. Pediatric Patients
Pediatric Patients
••
••
Higher proportion of water
Higher proportion of water
Lower plasma protein levels
Lower plasma protein levels
– More available drug
– More available drug
•• Immature liver/kidneys
Immature liver/kidneys
– Liver often metabolizes more slowly
– Liver often metabolizes more slowly
– Kidneys may excrete more slowly
– Kidneys may excrete more slowly
57. Geriatric Patients
Geriatric Patients
••
••
••
••
Chronic disease states
Chronic disease states
Decreased plasma
Decreased plasma
protein binding
protein binding
Slower metabolism
Slower metabolism
Slower excretion
Slower excretion
••
••
Dietary deficiencies
Dietary deficiencies
Use of multiple
Use of multiple
medications
medications
•• Lack of compliance
Lack of compliance
58. Web Resources
Web Resources
•• Basic Pharmacokinetics on the Web
Basic Pharmacokinetics on the Web
– http://pharmacy.creighton.edu/pha443/pdf/Defa
– http://pharmacy.creighton.edu/pha443/pdf/Defa
ult.asp
ult.asp
•• Merk Manual: Overview of Drugs
Merk Manual: Overview of Drugs
– http://www.merck.com/pubs/mmanual_home/se
– http://www.merck.com/pubs/mmanual_home/se
c2/5.htm
c2/5.htm
59. Web Resources
Web Resources
•• Merk Manual: Factors Affecting Drug
Merk Manual: Factors Affecting Drug
Response
Response
– http://www.merck.com/pubs/mmanual_home/se
– http://www.merck.com/pubs/mmanual_home/se
c2/8.htm
c2/8.htm
•• Merk Manual: Pharmacodynamics
Merk Manual: Pharmacodynamics
– http://www.merck.com/pubs/mmanual_home/se
– http://www.merck.com/pubs/mmanual_home/se
c2/7.htm
c2/7.htm