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N926: Pharmacology > Pharmacokinetics > Flashcards

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

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2
Q

Pharmacokinetics Processes

A 
Absorption 
Distribution
Metabolism 
-Metabolites 
Excretion 
-Drug 
-Metabolites
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3
Q

Elimination includes

A

Metabolism and excretion

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4
Q

Factors influencing PK activity

A 
Ionization and lipid solubility 
Ion trapping 
Protein binding 
Molecular size
Drug transporters
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5
Q

Drugs that work most effectively in anesthesia

A

Get through the blood brain barrier fastest

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6
Q

Lipophilic/hydrophobic drug

A

Unionized/nonionized
No charge
(Gets BBB)

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7
Q

Hydrophilic/Lipophobic drug

A

Ionized
Charge
(Does not get through BBB, )

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8
Q

Protonated

A

To add a proton

aka adding H+

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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.

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10
Q

Acids are usually defined as

A

“proton donors”

pitchers

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11
Q

Bases are usually defined as

A

“proton acceptors”

catchers

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12
Q

pH-pKa=0

A

50:50

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13
Q

pH-pKa=0.5

A

75:25

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14
Q

pH-pKa=1

A

99:1

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15
Q

Acids in acidic pH

A

Non-ionized

Lipophilic

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16
Q

Bases in basic pH

A

Non-ionized

Lipophilic

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17
Q

Acids in basic pH

A

Ionized

Hydrophilic

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18
Q

Bases in acidic pH

A

Ionized

Hydrophilic

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19
Q

Nonionized charge

A

No charge

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20
Q

Are nonionized pharmacologic effects active or inactive?

A

Active

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21
Q

What are nonionized soluble in?

A

Lipids

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22
Q

Do nonionized readily cross membranes?

A

Yes

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23
Q

Do nonionized undergo tubular reabsorption?

A

Yes

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24
Q

Do nonionized undergo renal excretion?

A

No

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25
Q

Do nonionized undergo hepatic metabolism?

A

Yes

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26
Q

Do ionized have a charge?

A

Yes

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27
Q

Are ionized pharmacologic effects active or inactive?

A

Inactive

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28
Q

Do ionized readily cross membranes?

A

No

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29
Q

Do ionized undergo tubular reabsorption?

A

No

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30
Q

Do ionized undergo renal excretion?

A

Yes

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31
Q

Do ionized undergo hepatic metabolism?

A

No

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32
Q

Ion trapping

A

Influences the absorption of drugs, maternal-fetal transfer and CNS toxicity of local anesthetics

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33
Q

Molecular size

A 
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
Q

Protein binding slide notes

A

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
Q

Protein binding lecture notes

A

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
Q

Drug transporters

A 
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
Q

Antiport

A

the exchange of one molecule for another

38
Q

Symport

A

transport of two molecules together

39
Q

Absorption: bioavailability

A

Bioavailability is the amount of drug that is able to produce its effect after entering the body

40
Q

Factors that influence bioavailability

A
  • Drug factors
  • Patient factors
  • First-pass effect
41
Q

Intravenous bioavailability

A

100%

Most rapid onset

42
Q

First-pass effect

A 
Seen with enteral administration
• Not sublingual or rectal
GI tract to portal circulation
• Decreases bioavailability
-Adjustments in dosing
-Alternate route of administration
43
Q

Distribution

A

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
Q

One-compartment model

A

• Represents entire body; homogeneous distribution throughout
-Beaker example with dye

45
Q

Two-compartment model

A

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
Q

Drugs leave the central compartment in two phases

A

Distribution
• Alpha half-life
Metabolism and excretion
• Beta half-life

47
Q

Volume of distribution (Vd)

A

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
Q

Normal Vd for a 70kg patient is

A

42L or 0.6 L/kg

49
Q

Large Vd is

A

> 0.6 L/kg

50
Q

Small Vd

A

<0.4 L/kg

51
Q

Special distribution issues

A 
Blood brain barrier
• Tight junctions
• P-gp
• Small molecules 
• Lipophillic
Elderly 
Placenta 
Breast milk
52
Q

Metabolism

A

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
Q

First order kinetics

A

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
Q

Zero order kinetics

A

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
Q

Phase I metabolism

A

result in increased polarity; lipid soluble to water-soluble
• Oxidation
• Reduction
• Hydrolysis

56
Q

Phase II metabolism

A

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
Q

Oxidation

A

Oxygen introduced into the molecule
• Catalyzed by cytochrome (CY) P-450 enzymes
• Results in a loss of electrons

58
Q

Reduction

A

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
Q

Hydrolysis

A

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
Q

CYP-450 Enzymes

A

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
Q

Enzyme Induction

A

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
Q

Enzyme Inhibition

A

Exposure to certain drugs leading to an accumulation of agent (grapefruit juice)
• Elevated plasma levels
•Potential for increased drug activity or toxicity

63
Q

Elimination

A

Removal of drug from the body
Metabolism + excretion
Possibilities
• Metabolism, excretion unchanged, or some of both

64
Q

Factors affecting elimination

A
  • Properties of the drug
  • Organ function
  • Concomitant medications
  • Genetic variations
65
Q

Clearance

A

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
Q

How is rate of clearance determined?

A

by blood flow to the liver and kidney and their ability to extract drug from the blood

67
Q

Hepatic clearance: Perfusion dependent elimination

A

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
Q

Hepatic clearance: Capacity dependent elimination

A

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
Q

Elimination Half-Life

A

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
Q

Context sensitive half-time

A

Time required for an infusion maintained at a constant concentration to decrease by 50%
Increases with longer infusions

71
Q

Excretion

A

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
Q

Elderly

A
  • Decreased renal function
  • Decreased liver blood flow
  • Increased fat stores
  • Increased Vd
73
Q

Neonates

A

Immature liver enzymes

74
Q

Female

A
  • More sensitive to paralytics
  • Quicker emergence, more likely to have recall
  • Experience adverse effects of opioids
75
Q

Male

A

• More sensitive to propofol

76
Q

CKD

A
  • Reduced clearance and elimination

* Impairment of protein binding, metabolizing enzymes and drug transporters

77
Q

Chronic liver disease

A
  • 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
Q

Pharmacogenetics

A

is the study of variation in human genes that are responsible for different responses to drug therapy

79
Q

Pharmacogenomics

A

involves the identification of drug response markers at the level of disease, metabolism or target

80
Q

Polymorphisms

A

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

N926: Pharmacology (4 decks)

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