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Pharmacology (MPAS) > Lecture 2: Pharmakokinetics > Flashcards

Lecture 2: Pharmakokinetics Flashcards

1
Q

What is pharmakokinetics?

A

The study of how the body absorbs, distributes, metabolizes, and eliminates (ADME) a drug over time

The application of mathematical formulas to ADME

How drugs move through the body

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2
Q

Primary sites of ADME

A

Mouth (some absorption)

Stomach (some absorption, 1st pass effect)

Small intestine (primary site of absorption)

Kidney (primary site of excretion)

Liver (primary site of metabolism)

Blood (distribution)

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3
Q

Uses of PK

A

– Apply PK principles to clinical practice

– Determine rates of ADME, etc.

– Calculate the bioavailability percentage

– Predict plasma (blood) concentrations related to drug dose

– Optimize dose regimens for best efficacy/toxicity

– Assess factors that may alter drug disposition (metabolism)

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4
Q

Clinical goal of PK?

A

Enhancing efficacy and decreasing toxicity

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5
Q

Interrelationships of ADME

A

Bound drug is restricted

Interactions between compartments

(see figure)

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6
Q

From dose to effect

A

See figure

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7
Q

Routes of administration for drug

A
  • Oral
  • IV
  • Subcutaneous
  • Intramuscular
  • Transdermal patch
  • Rectal
  • Inhalation
  • Sublingual

See figure

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8
Q

How do drugs cross cell membranes? (essential to move through body)

A
  1. passing through channels or pores
  2. passing through the membrane with the aid of a transport system, or
  3. penetrating directly
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9
Q

Where are transporters found?

A

Liver

Kidneys

Intestines

Brain capillaries

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10
Q

What is the most common way that drugs cross the membrane?

A

Direct penetration

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11
Q

What does the movement through the body depend on for most drugs?

A

Ability to penetrate membranes directly

Most drugs are too large to pass through channels

Most drugs lack transport systems to help them cross the membrane

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12
Q

What characteristic must a drug have to penetrate cell membranes directly?

A

Lipid soluble

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13
Q

One-compartment model of drug disposition

A

Whole body is compartment.

Drugs that do not extensively distribute into extravascular tissues

Not realistic, but is an approximation

See figure

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14
Q

Two compartment model of drug disposition

A

Drugs that do extensively distribute in tissue

See figure

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15
Q

Key parameters in PK

A

Bioavailability

Drug Accumulation

Volume of Distribution - Vd

Clearance

Drughalf-life-T1/2

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16
Q

Bioavailability def

A

the fraction of unchanged drug reaching the systemic circulation following administration by any route

Measures absorption

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17
Q

Drug accumulation def

A

drug accumulation is inversely proportional to dose lost (elimination)

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18
Q

Volume of distribution (Vd) def

A

the measure of the apparent space in the body available to contain
the drug – how drug is distributed in body relative to plasma

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19
Q

Clearance def

A

the measure of the ability of the body to eliminate the drug

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20
Q

Drug half life (T1/2)

A

the time required to change the amount of drug in the body by one- half during elimination

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21
Q

Inverse relationships of accumulation and elimination

A

At one half-life, 50% of drug has accumulated/been eliminated

2 half lives, 75% of drug has accumulated, 75% eliminated

5 half lives to reach plateau

See figure

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22
Q

Bioavailability formula

A

Bioavailability= (AUCadminroute/AUCIV)x100

IV administration is used as a reference

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23
Q

Drug accumulation formula

A

Accumulation factor = 1 / dose lost (ie, the elimination fraction)

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24
Q

Volume of distribution formula

A

VD = Amount of drug in body (mg) / Concentration of drug in plasma

(mg/L - quotient expressed in L)

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25
Q

Clearance formula

A

CL = (0.693 / t 1⁄2 ) x VD

0.693 = natural log constant

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26
Q

Determination of drug absorption

A
  1. Timetopeakconcentration - Rate
  2. Peak concentration - Rate and extent
  3. Area under the plasma concentration vs time curve (AUC) - Extent

See figure

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27
Q

What does the area indicate on a plasma concentration vs time graph

A

Area reflects extent of absorption of drug

Area reflects actual body exposure to drug

See figure

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28
Q

Routes of administration and bioavailability

A

Decreasing bioavailability: IV, transdermal, IM, SC, rectal (PR), Oral (PO), inhalation

See figure

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29
Q

Admin route with most rapid onset

A

IV

Inhalation, but range of bioavailability is greater

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30
Q

Which admin route is most convenient

A

Oral

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31
Q

Which admin route has prolonged duration?

A

Transdermal patch

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32
Q

Limitations of drug absorption

A

Tissue perfusion (Blood flow)

Diffusion-limited absorption - Partition coefficient (a measure of the difference in solubility of the compound in 2 phases, eg, water/membrane interface)

First pass effect

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33
Q

What is the first pass effect?

A

Rapid liver inactivation of oral drugs

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34
Q

What is enterohepatic cycling?

A

Recycling of drug through vessels and organs so that drug can be further utilized. Drug gets another chance to do its job. (kind of like the opposite of the first pass)

Thanks to bile duct

Reduces elimination

Prolongs t1⁄2

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35
Q

Factors influencing drug absorption

A

Formulation

Watersolubility

Lipidsolubility

pKa

GI motility

Posture

Otherdrugs/foods • GastricpH

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36
Q

What is ion trapping?

A

an acidic drug will be non-ionized in acid media and ionized in alkaline media.

example: aspirin (an acidic drug) dissolves in stomach (in acidic compartment, pH=1 to 2) and gives up a H+, and then uncharged species passes across membrane to a basic environment (plasma pH=7.4)

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37
Q

Ion trapping of acidic and basic drugs

A

See figure

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38
Q

Relationship of pH and pKa

A

pH < pKa: protonated form of drug

pH > pKa: deprotonated form of drug

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39
Q

What is the henderson hasselbach equation?

A

a relationship between pKa and ratio of acid-base concentrations to pH

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40
Q

What can HH equation be used for?

A

determining how much drug on each side of membrane

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41
Q

What is pKa?

A

measure of the strength of the interaction of a drug (compound) with a proton

pH is a measure of hydrogen (H) ion concentration (acids have more H)

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42
Q

Why do drugs pass through membranes in stomach easier uncharged?

A

The stomach is acidic (pH 1 to 2) and acidic drugs don’t ionize in acid compartments, so drugs pass thru membranes in stomach more easily uncharged

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43
Q

Why do drugs pass through membranes in intestines easier uncharged?

A

The intestine is more basic (pH sm. int.=8.5, lg. int. =5.5 to 7)and basic drugs don’t ionize in basic mediums, so drugs pass thru membranes in intestine more easily uncharged

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44
Q

Example of acidic drug

A

Aspririn

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45
Q

How to attain steady state?

A

AKA therapeutic window

Sweet spot of drug concentration in plasma

Attained by continuous IV infusion

Steady state achieved when rate of drug
elimination equals rate of administration

Boundaries: toxic plasma level, minimum effective plasma level

See figure

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46
Q

Plasma concentration during frequent and infrequent dosing

A

See figure

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47
Q

What is the most common protein for bound drug?

A

Albumin

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48
Q

Bound vs unbound drug

A

Only unbound drug can leave vessels

Bound drugs are too big

A lot of bound drug can alter distribution times

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49
Q

Volume of distribution (need to look up)

A

the measure of the apparent space in the body available to contain the drug – how drug is distributed in body relative to plasma

= total amount of drug in body/plasma concentration

not a real volume or space, but rather a calculated value used to determine the tissue distribution of a drug

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50
Q

What can you use Vd for?

A

Needed for determining clearance of a drug from the body

Needed for determining loading dose of a drug

A high Vd means that drug not staying in vascular compartment (ie, extensively distributed)

Vd might actually surpass body fluid vol.

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51
Q

Formula for loading dose

A

Loading dose = Vd x desired plasma conc

52
Q

Loading dose vs no loading dose

A

See figure

Loading dose is higher than maintenance dose

53
Q

Dosing rate formula

A

Dosing Rate = CL x TC (or target concentration-plasma)

= (vol / time) (amt / vol) = amt / time

54
Q

Formula for maintenance dose

A

Maintenance Dose = (Dosing Rate/F) x Dosing Interval

= (amt / time) (time)

= amount

Where F = fraction absorbed (bioavailability)

55
Q

Formula for loading dose

A

Loading Dose = VD x TC (assuming F close to 1)

= (VD x TC ) / F

56
Q

Factors influencing drug distribution in the body

A

pKa of compound and pH of tissue compartment

acidic drugs more likely to be concentrated in blood compartment

basic drugs more likely to be concentrated in tissue

Drug binding

Specialized distribution barriers (BBB, placenta)

57
Q

Drug metabolites vs parent compound

A

Drug metabolites are usually more polar than their parent compound

58
Q

Drug metabolizing enzyme expression

A

Expression differs among tissue type

59
Q

Phase 1 metabolism reactions

A

Oxidation, Reduction, hydrolysis

60
Q

Phase 2 metabolism reactions

A

Conjugation:

Glucuronidation

Sulfation

Acetylation

61
Q

Phase 1 and Phase 2 reactions diagram

A

See figure

62
Q

Pathways of drug transportation

A

See figure

Some drugs become more hydrophilic

Some drugs skip phase I

Some drugs become less active or activity changes

63
Q

First order metabolism

A

Most drugs 1st order

Rate of drug metabolism proportional to dose

64
Q

Zero order metabolism

A

e.g., aspirin, ethanol

Enzyme is saturated

Rate of drug metabolism remains constant over time

65
Q

First order and zero order reactions diagramX

A

See figure

66
Q

Therapeutic Consequences of Phase I and Phase II Metabolism

A

Accelerated renal excretion

Drug inactivation

Activation of prodrugs

Decreased toxicity (not always true)

Increased therapeutic action

Increased toxicity

67
Q

How to calculate total clearance

A

Need to add clearances for all organs together (see figure)

68
Q

What is the importance of Cl

A

Provides an index of the efficiency by which a drug is removed from the body

Is subject to changes due to disease state, genetic and environmental factors

Needed for determining Dosing Rate and Maintenance Dose.

69
Q

Clearance in elderly people

A

Clearance is slower

slower exrcetion, prolonged action in the body

so we can use a lower dose

70
Q

Clearance in Relationship to Drug Elimination

A

Clearance (Cl) – the volume of plasma that would contain the amount of drug excreted per unit time (minutes)

Volume of plasma that would have to lose all of the drug that it contains within a unit of time (usually 1 min) to account for an observed rate of drug elimination

Clearance expresses the rate or efficiency of drug removal from the plasma vol/time (ml/min)

Cl = ke (Vd) or Cl = (0.693/t1/2) * Vd

71
Q

How many half-lives are required to eliminate a single dose of a drug from the body?

A

Five half lives

See figures

72
Q

What is half life?

A

The time it takes for drug concentration in plasma to decline by 50%

t1/2 = 0.693/ke

73
Q

What order is most drug PK?

A

Most drug PK is first order - equal proportion of drug is removed per unit time

74
Q

Renal elimination of drugs

A

Low MW drugs enter kidney (via renal artery)

Lipid soluble drugs move back into blood

Non-lipid soluble, polar, and ionized drugs remain in urine

3 steps (glomerular filtration, tubular reasborption, tubular secretion)

See figure

75
Q

What is used to assess renal impairment?

A

Creatinine clearance

76
Q

What does metabolism do to activity of drug?

A

Metabolism often removes biological activity, but can also result in active drug

77
Q

What would make a small Vd?

A

If concentration of drug in plasma is high. For example, if the drug is trapped in the plasma compartment (such as very strong binding to serum albumin) = measured concentration would be high

78
Q

What would make a high Vd?

A

If drug is sequestered from the plasma into lipid as a result of the drug being highly lipid soluble.

Concentration in plasma will be low and Vd will go up

79
Q

What is a pitfall of using Vd?

A

Does not give an indication of where the drug is anatomically

80
Q

What are two other factors that affect Vd?

A

how lipid soluble the drug is and whether it binds to tissue proteins.

Both of these factors increase the drugs volume of distribution because the drug is NOT in the plasma or blood compartment.

81
Q

Factors that effect Vd and their effect on half life

A

Ageing (decr muscle) - decr T1/2

Obesity (incr adipose) - incr T1/2

Pathologic fluid - incr T1/2

82
Q

Factors effecting Cl and their effect on T1/2

A

Induction of Cyp450 - decr T1/2

Inhibition of Cyp450 - inc T1/2

Organ failure - inc T1/2

83
Q

Inter-relationship between Half-life, Vd and Clearance

A

Cl=(0.693/t1/2)*Vd

t1/2 = [(0.693) * Vd] /Cl

84
Q

Drug transporting proteins

A

Organic anion transport proteins (OATs or OATPs)

Organic cation transport proteins (OCTs) - New nomenclature - Solute Carrier (SLC) transporters

P-glycoprotein (P-gp or MDRs)

MRP - multidrug resistance-associated proteins

85
Q

Why is the location of a drug transporter important?

A

Determines function

86
Q

Renal drug transporters important for elimination substrates

A

OCT’s- TEA

OAT’s- alpha KG

Oatp’s- sulfobromophthalein

MDR-verap/CsA/Elacridar

MRP’s- indo

87
Q

What is the major route for drug elimination for most drugs?

A

Renal excretion

88
Q

3 steps of drug excretion

A

Glomerular filtration

Tubular reabsorption

Tubular secretion

89
Q

What is a prodrug?

A

Inactive form of a drug that needs to be activated to have effect

Often activated by metabolism, which increases bioavailability

90
Q

What are the hepatic drug metabolizing enzymes?

A

Microsomal enzyme system

aka: P450 system

91
Q

Families of P450 system

A

12 families

3 of these families metabolize drugs (CYP1,2,3)

9 of these families metabolize sterioids and fatty acids, etc.

92
Q

CYP nomenclature

A

Family: CYP1, 2, 3

Subfamily: added letters

Gene/isoenzyme: added numbers

See figure

93
Q

Proportion of drugs metabolized by CYP 450

A

Majority by CYP 34A/5 and CYP 2D6

See figure

94
Q

Drug inducers and inhibitors

A

Different CYP subfamilies are affected by different inducers and inhibitors

Inducers increase CYP activity, less active drug available

Inhibitors decrease CYP activity, more drug available

See figure

95
Q

Acetominophen, cocaine and testosterone inducers

A

Inducer: St. John’s wort

Inhibitor: Grapefruit juice

Need to be careful!

96
Q

Where in metabolism do CYP 450 enzymes have the biggest role?

A

Phase II reactions

97
Q

Examples of drugs altered in phase II reactions by CYP enzymes

A

Morphine -> morphine-6-gluro (pain reduction)

Minoxidil -> minoxidil sulfate (for hair growth)

Procainamide -> N-acetylprocainamide (for arrhythmia)

98
Q

Transformation of morphine

A

See figure

Many CYPs involved

99
Q

Examples of drugs that induce enzymes

A

Phenytoin: anticonvulsant medication. Overtime, causes increased expression of various cyp450 enzymes (cyp34A)

Rifampicin: antimicrobial, induces cyp450

100
Q

Importance of induction

A

Mechanism that allows enzyme to change in response to xenobiotic

dynamic system that can respond to environment

101
Q

Importance of induction from drug standpoint

A

PK- increased clearance; decreased half-life

PD- decreased response

102
Q

Inducers and alterations of PK parameters

A

AUC: decreases (less bioavailable)

Cl (L/h): increases

T1/2: decreases

Cmax (max serum conc): decreases

Tmax (amount of time that drug is at max conc): increases

103
Q

Other than drugs, what other factors can cause induction of enzymes?

A

environment/lifestyle factors (smoking)

herbal and nutritional supplements

104
Q

Cimetidine as an enzyme inhibitor

A

Cimetidine-H2 receptor agonist

Used to treat peptic ulcer

Potent inhibitor of several cyp250 enzymes

Drug interactions: warfarin, benzodiazepines, phenytoin, morphine

105
Q

PK and PD effects of cimetidine

A

PK: decreased Cl, increased T1/2

PD: increased response, increased duration

106
Q

Enzyme inhibitor types of drug interactions

A

Drug A blocks metabolism of drug B

PD: increase response

PK: increase t1/2

Effects are immediate

107
Q

Enzyme inducer types of drug interactions

A

Drug increases amt of enzymes for metabolism

Decreased response

Decrease plasma t1/2

Effects are delayed

108
Q

Examples of inducers

A

Ethanol

Omeprazole

Phemobarbital

Rifampin

Smoking

109
Q

Examples of inhibitors

A

Cimetidine

Erythromycin

Grapefruit juice

Ketoconazole

Quinidine

110
Q

What are the three gene families under pressure for genetic variations

A

CYP gene family

UDP glucoronosyl transferase

N-acetyl transferase

111
Q

CYP gene family genetic variations

A

Expression level

Enzyme Activity

Enzyme Induction

112
Q

UDP glucoronosyl transferase genetic variability

A

Activity

113
Q

N-acetyl transferase genetic variability

A

Expression level

114
Q

CYP polymorphisms

A

see figure

115
Q

CYP2D6 alleles

A

43 total (as of 2004)

24: no activity
6: decreased activity
* 2 variant can have 1,2,3,4,5 or 13 copies (increased activity)

116
Q

CYP2D6 phenotype variation by race

A

caucasians highest frequency of PM phenotype

asians highest frequency of IM phenotype

africans highest frequency of the UM phenotype

117
Q

Nortriptyline and CYP2D6

A

Active metabolite of nortryptiline is 10-hydroxynortriptlyline

Increasing number of copies of prodrug results in quicker elimination

Opposite for active drug

118
Q

CYP2D6 and codeine - importance of genetic variability

A

Codeine -> morphine

0 copies: no metabolism, codeine is ineffective and maybe toxic

1-3 copies: adequate pharmacological response

13 copies: overdose?

119
Q

Adverse responses to procainamide in slow and fast acetylators

A

Procainamide is used for tachycardia, but causes lupus

Slow acetylators develop adverse events more quickly

120
Q

Reasons for variations in drug metabolism

A

Due to induction – other drugs, environment

Due to diet – natural inducers and inhibitors

Due to inhibition – disease processes and drugs

Due to genetics – defect in metabolic pathways

Due to development – special populations

Due to disease – impairment of organ function

121
Q

How does age effect drug disposition?

A

Rate of drug disposition is most likely impaired in very young and very old

122
Q

Importance of personalized medicine

A

Different patients have different expression of drug metabolizing enzymes, different diets and different backgrounds

123
Q

Which organ if it became dysfunctional would be the most likely to affect drug metabolism?

A

Liver

124
Q

Name two routes of drug administration that would be subject to 1st pass metabolism?

A

Oral

Rectal

125
Q

What are the three outcomes of drug metabolism? Which is most common?

A

??

126
Q

Routes of administration that avoid the 1st pass effect

A

suppository

intravenous

intramuscular

inhalational aerosol

transdermal

sublingual

Pharmacology (MPAS) (19 decks)

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