Pharmacokinetics Flashcards
1
Q
Pharmacokinetics
A
What the body does to the drug
Actions of the body on the drug
What the body does to a drug once the agent has been introduced into the system
2
Q
Pharmacokinetics Processes
A
Absorption Distribution Metabolism -Metabolites Excretion -Drug -Metabolites
3
Q
Elimination includes
A
Metabolism and excretion
4
Q
Factors influencing PK activity
A
Ionization and lipid solubility Ion trapping Protein binding Molecular size Drug transporters
5
Q
Drugs that work most effectively in anesthesia
A
Get through the blood brain barrier fastest
6
Q
Lipophilic/hydrophobic drug
A
Unionized/nonionized
No charge
(Gets BBB)
7
Q
Hydrophilic/Lipophobic drug
A
Ionized
Charge
(Does not get through BBB, )
8
Q
Protonated
A
To add a proton
aka adding H+
9
Q
pKa
A
The ionization constant of a chemical compound.
By definition it is the pH at which a drug will exist as 50% ionized and 50% unionized.
pKa does not measure acid or base status; rather extent of ionization.
10
Q
Acids are usually defined as
A
“proton donors”
pitchers
11
Q
Bases are usually defined as
A
“proton acceptors”
catchers
12
Q
pH-pKa=0
A
50:50
13
Q
pH-pKa=0.5
A
75:25
14
Q
pH-pKa=1
A
99:1
15
Q
Acids in acidic pH
A
Non-ionized
Lipophilic
16
Q
Bases in basic pH
A
Non-ionized
Lipophilic
17
Q
Acids in basic pH
A
Ionized
Hydrophilic
18
Q
Bases in acidic pH
A
Ionized
Hydrophilic
19
Q
Nonionized charge
A
No charge
20
Q
Are nonionized pharmacologic effects active or inactive?
A
Active
21
Q
What are nonionized soluble in?
A
Lipids
22
Q
Do nonionized readily cross membranes?
A
Yes
23
Q
Do nonionized undergo tubular reabsorption?
A
Yes
24
Q
Do nonionized undergo renal excretion?
A
No
25
Do nonionized undergo hepatic metabolism?
Yes
26
Do ionized have a charge?
Yes
27
Are ionized pharmacologic effects active or inactive?
Inactive
28
Do ionized readily cross membranes?
No
29
Do ionized undergo tubular reabsorption?
No
30
Do ionized undergo renal excretion?
Yes
31
Do ionized undergo hepatic metabolism?
No
32
Ion trapping
Influences the absorption of drugs, maternal-fetal transfer and CNS toxicity of local anesthetics
33
Molecular size
```
The smaller the size, the more likely it will pass through lipid barriers and membranes
• >100-200 amu do not cross
Requires active transport mechanisms
• Faster
• Requires energy
```
34
Protein binding slide notes
Changes in protein binding have long been theorized to influence a drug’s effect
• Patient with reduction in proteins (Liver or kidney disease, poor nutrition, last trimester of pregnancy)
• Drug interaction between two highly protein bound drugs
Albumin is most prominent protein; preferential bond with acids
Alpha1-acid protein preferentially bonds with bases
• Extensive binding slows drug elimination (metabolism and excretion by filtration)
35
Protein binding lecture notes
*Drugs that are more lipophilic tend to bind to plasma proteins more*
If drugs are bound to a protein they can't go into effect and they cannot cross the BBB.
Drugs are redistributed when they are bound to plasma protein, they fall off plasma protein when plasma concentration drops but it is not enough to go into effect.
Think propofol example-half life of 11 hours.
36
Drug transporters
```
Facilitate small molecule transport
• Over 300 genes code these transporters
• Transport endogenous substances and drugs
Classified as:
• Efflux – drive substrate out of cell
• Intake – transfer into cells
```
37
Antiport
the exchange of one molecule for another
38
Symport
transport of two molecules together
39
Absorption: bioavailability
Bioavailability is the amount of drug that is able to produce its effect after entering the body
40
Factors that influence bioavailability
* Drug factors
* Patient factors
* First-pass effect
41
Intravenous bioavailability
100%
| Most rapid onset
42
First-pass effect
```
Seen with enteral administration
• Not sublingual or rectal
GI tract to portal circulation
• Decreases bioavailability
-Adjustments in dosing
-Alternate route of administration
```
43
Distribution
Compartmental models are theoretic spaces with calculated volumes used to describe the PK of agents
• Prediction of serum concentrations and other tissues
In reality, compartments are NOT TRUE anatomic areas
• Conceptual representations of two separate volumes
44
One-compartment model
• Represents entire body; homogeneous distribution throughout
-Beaker example with dye
45
Two-compartment model
Central compartment; vasculature and vessel-rich tissues (heart, brain)
• 10% of body mass, but 75% of cardiac output
Peripheral compartment; muscle fat and bone
• 90% of body mass, but only 25% of cardiac output
46
Drugs leave the central compartment in two phases
Distribution
• Alpha half-life
Metabolism and excretion
• Beta half-life
47
Volume of distribution (Vd)
The degree to which drugs distribute and redistribute, and the resultant concentration established before elimination is used to calculate the volume of distribution (Vd)
A proportional expression relating the amount of drug in the body to the serum concentration
48
Normal Vd for a 70kg patient is
42L or 0.6 L/kg
49
Large Vd is
>0.6 L/kg
50
Small Vd
<0.4 L/kg
51
Special distribution issues
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Blood brain barrier
• Tight junctions
• P-gp
• Small molecules
• Lipophillic
Elderly
Placenta
Breast milk
```
52
Metabolism
Aka...biotransformation - enzyme-catalyzed change in chemical structure
Liver is the main organ of metabolism
• Plasma, lungs, GI tract, kidneys, heart, brain, and skin
GOAL – convert lipid soluble agents into water soluble forms ***Take unionized drugs and make them ionized***
• Allows for renal elimination
First-order vs. zero-order kinetics
Metabolism occurs in two phases:
• Phase I
• Phase II
53
First order kinetics
The drug is cleared at a rate proportional to the amount of drug present in the plasma.
* Occurs for most drugs at therapeutic doses
* Drug cleared at a rate proportional to amount present in plasma
* Greatest amount clears when plasma concentration is highest
54
Zero order kinetics
A constant amount of drug is cleared regardless of the plasma concentration.
The available enzyme systems for elimination are saturated.
Drugs such as alcohol exceed the body's ability to excrete or metabolize them even at therapeutic levels.
55
Phase I metabolism
result in increased polarity; lipid soluble to water-soluble
• Oxidation
• Reduction
• Hydrolysis
56
Phase II metabolism
drug or metabolite conjugated with endogenous substance (glucuronic, sulfonic or acetic acid)
• Conjugation
Once drug molecule get to the kidney, too big can't be reabsorbed, gets excreted
57
Oxidation
Oxygen introduced into the molecule
• Catalyzed by cytochrome (CY) P-450 enzymes
• Results in a loss of electrons
58
Reduction
CYP-450 enzymes transfer enzymes directly to the substrate
• Occurs when insufficient oxygen available to compete for electrons
• Results in a gain of electrons
59
Hydrolysis
addition of water to an ester or amide to break the bond into two smaller molecules
• Leads to an acid and alcohol (ester)
• Leads to an acid and amine (amide)
60
CYP-450 Enzymes
CYP-450 microsomal enzymes are found in the smooth endoplasmic reticulum of the liver
• Cytochrome – (iron-containing hemoprotein)
• 450 – indicates peak absorption of 450 nm when reacting with carbon
monoxide
Aka...mixed-function oxidase system
There are six well-characterized forms
• CYP3A4 most common
• CYP2D6 required to convert codeine and tramadol to active opioid
61
Enzyme Induction
An increase in activity by stimulating enzymes over a period of time
• Chronic alcohol abuse induces enzymatic activity
-More drug needed to obtain same effect
• Enzymes quickly break agents down, leading to a reduction in half-life
62
Enzyme Inhibition
Exposure to certain drugs leading to an accumulation of agent (grapefruit juice)
• Elevated plasma levels
•Potential for increased drug activity or toxicity
63
Elimination
Removal of drug from the body
Metabolism + excretion
Possibilities
• Metabolism, excretion unchanged, or some of both
64
Factors affecting elimination
* Properties of the drug
* Organ function
* Concomitant medications
* Genetic variations
65
Clearance
Volume of plasma completely cleared of drug by metabolism and excretion
• Independent value governed by:
-Drug properties
-Body’s ability to clear it
Directly proportional to the dose and inversely related to half-life
• Two main organs of clearance: liver and kidney
66
How is rate of clearance determined?
by blood flow to the liver and kidney and their ability to extract drug from the blood
67
Hepatic clearance: Perfusion dependent elimination
Drugs that are highly dependent on perfusion; “high” extraction ratio (0.7 or greater)
These drugs are referred to as ”high-clearance drugs”
• Verapamil, morphine and lidocaine
Decrease in perfusion equals decreased clearance and vice versa
68
Hepatic clearance: Capacity dependent elimination
Small amount of drug removed per unit of time; “low” extraction ratio. (less than 0.3)
• Hepatic perfusion does not have significant effect on clearance
Clearance dependent on hepatic enzymes and protein binding
• Induction causes faster elimination and vice versa
• Decreased protein binding leads to great clearance
• Diazepam and theophylline
69
Elimination Half-Life
Time necessary for plasma concentration of a drug to decrease by half following a rapid bolus injection
• Most drugs follow first-order kinetics (constant rate)
• It takes the same amount of time to reduce a concentration from 100mg to 50mg
as it does from 10mg to 5mg
• For practical purposes, a drug is considered eliminated when 95% is
removed from the body
• Four to five half-lives
• Too frequent of dosing can cause accumulation
70
Context sensitive half-time
Time required for an infusion maintained at a constant concentration to decrease by 50%
Increases with longer infusions
71
Excretion
The excretion of drugs by the kidney involves:
-Passive glomerular filtration
• Water soluble metabolites are filtered and eliminated
• Aminoglycoside antibiotics
-Active tubular secretion
• Penicillin
-Reabsorption
• Lipid soluble molecules are reabsorbed and placed back into circulation (propofol)
72
Elderly
* Decreased renal function
* Decreased liver blood flow
* Increased fat stores
* Increased Vd
73
Neonates
Immature liver enzymes
74
Female
* More sensitive to paralytics
* Quicker emergence, more likely to have recall
* Experience adverse effects of opioids
75
Male
• More sensitive to propofol
76
CKD
* Reduced clearance and elimination
| * Impairment of protein binding, metabolizing enzymes and drug transporters
77
Chronic liver disease
* Cirrhosis – all processes may be altered
* High portosystemic pressure impedes GI absorption
* Vd of protein bound drugs changed to hypoalbuminemia
* Ascites can also change Vd
* Phase I reactions can also be affected
78
Pharmacogenetics
is the study of variation in human genes that are responsible for different responses to drug therapy
79
Pharmacogenomics
involves the identification of drug response markers at the level of disease, metabolism or target
80
Polymorphisms
variations in the DNA sequences that occur in at least 1% of the population
• It is the most common cause of patient-to-patient variation in drug response
