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Pharmacology (Fall) > Pharmacokinetics & Drug Metabolism > Flashcards

Pharmacokinetics & Drug Metabolism Flashcards

1
Q

What is pharmacokinetics?

A

Greek: pharmakon- drug or poison and kinesis - motion

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

Helps us understand drug dose-effect relationship ◦ Target concentration to achieve therapeutic effect
◦ Increase THERAPEUTIC BENEFIT, decrease TOXICITY

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2
Q

Pharmacokinetics (PK) vs Pharmacodynamics (PD)

A

Pharmacokinetics
◦ What the body does to a drug
Dose → concentration

Pharmacodynamics
◦ What the drug does to the body Concentration → effect

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3
Q

What determines drug effect?

A

Drug concentration at the site of action
◦ Concentration at receptor sites determines the magnitude of the effect of a drug
◦Difficult to measure – inaccessible/widely distributed (why we use mathematical models)
◦Need to model

Another important consideration:
Drugs can accumulate in certain tissues/areas (e.g., fat)

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4
Q

Why should you care about PK?

A

Numerous important clinical uses
◦ To determine rates of absorption, metabolism and elimination
◦ To determine bioavailability (& diff. routes of administration)
◦ To predict plasma (blood) concentrations related to drug dose
◦ To optimize dose regimens
◦ To correlate activity (pharmacodynamics) with circulating drug concentration
◦ To assess factors that may alter drug disposition (age, gender, genetics, etc.)

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5
Q

Why should you care about PK?

Enhance _____ and prevent/decrease _____

A

efficacy

toxicity

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6
Q

What happens to a drug after it has been injected or swallowed?

A

Absorption, Distribution, Metabolism, Elimination

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7
Q

What is ADME?

A

Absorption
Distribution
Metabolism
Elimination

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8
Q

Absorption: how are drugs given?

A

◦ Intravenous (get into system quickest b/c go straight into bloodstream), intramuscular, subcutaneous
◦ Oral (go to stomach & then get absorbed in S.I.)
◦ Sublingual (under the tongue)
◦ Suppositories (e.g., rectal)
◦ Inhalation
◦ Topical
◦ Transdermal patch

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9
Q

Why are some drugs given by one route and other drugs given by another route?

A

b/c depends on how quickly you need it & what’s the site of action

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10
Q

If a rapid response is needed, what routes are best?

A

intravenous (IV) ?
b/c get into system quickest b/c go straight into bloodstream

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11
Q

What are the routes of administration: absorption patterns?

A

◦Oral
◦IV
◦ Subcutaneous
◦ Intramuscular ◦Transdermal patch
◦ Rectal
◦ Inhalation
◦ Sublingual

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12
Q

Where are ACID drugs absorbed?

A

in stomach b/c its acidic contents cause the acidic drugs to remain unionized/uncharged for easy absorption

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13
Q

Where are ALKALINE drugs absorbed?

A

in the intestine

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14
Q

What is the 1st pass metabolism?

A

some drugs are immediately metabolized in the liver

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15
Q

What is enterohepatic cycling?

A

other drugs may be secreted back into the S.I. in the bile
- other parts may be absorbed in the L.I. or fecally excreted

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16
Q

What is a major player in absorption?

A

the small intestine

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17
Q

The small intestine is…

A

Site of absorption after oral administration
◦Large surface area (about 1000 times that of the stomach)
◦Highly perfused (large blood flow); maintains a large concentration gradient from intestine to blood
- large area for drugs to enter & go through the blood circulation

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18
Q

Drug absorption requires…

A

drug permeation of cell membranes

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19
Q

______ molecules and _______ molecules have greater passive diffusion than charged molecules and hydrophilic molecules

A

UNcharged

LIPOphilic

If not, some drugs are membrane transport protein substrates ◦ Mechanism for absorption of charged and hydrophilic drugs

Many drugs are weak acids or weak bases and are charged or uncharged depending on pH
- diff. places in body has diff. pH so depends on the area if charged/uncharged

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20
Q

Only _____ molecules diffuse across lipid membranes

A

un-ionized

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21
Q

At LOW pH, ___ drugs are un-ionized and ___ are ionized

A

ACIDS

bases

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22
Q

pHgastric juice =

A

2.0

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23
Q

pHsmall intestine =

A

5.3

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24
Q

pHplasma =

A

7.4

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25
Q

What is pKa?

A

Measurement of the strength of the interaction of a compound with a proton
◦ The lower the pKa, the more acidic the compound and the stronger the acid
◦Drugs have different pKa pKa = -log10Ka
◦Ka acid disassociation constant

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26
Q

The lower the pKa, the more _____ the compound and the ______ the acid

A

ACIDIC

STRONGER

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27
Q

pKa:

A

pH when 50% of drug is ionized and 50% is not ionized

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28
Q

Video about stomach acid & drugs

A

Ion Trapping:
- SA’s in stomach, push WA drugs through a charge selective membrane without using energy
1. Simple Diffusion:
- will move from stomach –> blood
2. Charge Selective Mem.:
- uncharged can cross mem., but charged can NOT & get trapped
- charged trapped –> good b/c acid digests food in stomach
- uncharged cross –> bad if digestive acid gets in blood
3. Aspirin: uncharged or charged
- in blood: charged therefore cannot cross
- in stomach: scared by strong digestive acids so it’s uncharged therefore can cross
4. Ion Trapping:
- aspirin gets into stomach & takes uncharged form & crosses mem. & goes in blood where it converts to its charged form & is trapped
- gets aspirin in blood without using energy & to get an overdose of aspirin into basic urine

pH alters the charge of the drug & to get a drug over the mem. it has to be uncharged & since the pH in plasma is higher it’ll become charged & no longer able to go backwards now

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29
Q

Rate of drug absorption depends on numerous factors:

A
  • Formulation
  • Solubility (water/lipid)
  • pKa
  • Gastric pH
  • GI motility
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30
Q

GI motility:

Food –>

Emotions, exercise (sympathetic nervous system) –>

Rest (parasympathetic nervous system) –>

Cold fluids –>

A

◦ Decreases gastric emptying

◦ Decreases gastric emptying

◦ Increases gastric emptying

◦ Increases gastric emptying

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31
Q

Describe the inhalational barrier of absorption

A

Includes: nasal cavity, bronchial tree, lungs
Inhalation is used
◦ To treat local infections or diseases of the respiratory tract
◦ For systemic treatment – highly perfused organ with potential for rapid onset of drug action

Passive diffusion is primary route for absorption of drugs (gases or aerosols)

Alveoli are main site of absorption in lung

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32
Q

What are the factors influencing absorption in the lungs?

A

Drugs may be liquids, gases or aerosols

Partition coefficient: solubility in air vs solubility in blood (water)
◦ Important for gases

Particulate size (aerosols)
◦ Larger particles deposit in nasal cavity; those that travel further are often cleared by tracheobronchial removal
◦ Particles < 1μm are most likely to be absorbed

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33
Q

Most drugs are absorbed by _____ _____

A

passive diffusion

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34
Q

______ drugs have greater passive diffusion than charged drugs

A

UN-ionized

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35
Q

For drugs absorbed in the intestine, _____ ____ speeds up absorption

A

gastric emptying

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36
Q

Describe Distribution

A

◦ Drugs are distributed around the body in the blood

◦Depending on drug characteristics (size, ionization, lipophilicity), drugs may remain in blood or distribute to intercellular or intracellular compartments

◦Blood-brain barrier, blood-CSF barrier, blood-placenta barrier – restrict access of some drugs

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37
Q

What is Volume of Distribution (Vd)?

A

Key terms of importance in PK

◦ Measure of the apparent SPACE IN THE BODY available to contain the drug
◦ i.e., how homogenously a drug is distributed in body relative to plasma

Vd (L) = Amount of drug in body (mg)/Plasma concentration of drug (mg/L)

Note: not a real volume or space, but rather a calculated value used to
determine the tissue distribution of a drug.
- Therefore, can vastly exceed physical volume in the body.
- Depends on solubility, charge, size, etc.

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38
Q

What is the Vd for Drug A and Drug B? Why do Drug A and B have different Vd?

◦ Drug A: 200 mg dose; blood concentration is 20 mg/L
◦ Drug B: 200 mg dose; blood concentration is 2 mg/L

A

Drug A Vd = 10L
Drug B Vd = 100L

Drug B is higher [ ] in extra vascular tissue, therefore not homogeneously distributed in system (b/c less [ ] in blood so must be in other areas)

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39
Q

High Vd:

A

drug has higher concentrations in extravascular tissue compared to vascular compartment (not homogenous distribution)

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40
Q

Describe the Distribution: hypothetical models

A

a) stays constant b/c not eliminated
- therefore high [ ]
- once its distributed to other beaker it just stays constant b/c not eliminated

b) gets eliminated over time so therefore low [ ]

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41
Q

One-Compartment Model of Drug Disposition is the…

A

most commonly used model in clinical practice
- b/c it’s convenient

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42
Q

Why use compartment
models?

A

To PREDICT THE CONCENTRATION of a drug at any given time in any given body fluid or tissue

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43
Q

What is the Two-compartment model?

A

IV administration –> central and/or peripheral –> elimination

  • some drugs do not distribute instantaneously to all parts of body
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44
Q

What is the Multi compartment models?

A

◦A single compartment model is the least accurate

◦Adding more compartments may not necessarily improve the predictive value

◦All models have limitations

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45
Q

What are factors influencing drug distribution in the body?

A

Examples include:
1. pKa of drug and pH of tissue compartment
- b/c diff. tissue compartments differ in their pH

  1. Drug binding
  2. Specialized distribution barriers
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46
Q

Describe Specialized distribution barriers

A

1) Placental barrier
- in pregnant woman

2) Blood-brain barrier (BBB)
- in everyone

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47
Q

What does Vd indicate?

A

Vd indicates whether a drug accesses all body water or is
limited to blood

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48
Q

What affects Vd?

A

Size, charge, protein binding all affect Vd

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49
Q

Lipophilicity ___ passive diffusion of drug across barriers

A

↑
◦ e.g., blood-brain barrier, placenta

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50
Q

Some drugs are ____ in body compartments

A

stored
◦ e.g., fat, bone

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51
Q

Loading dose =

A

Vd x desired plasma concentration

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52
Q

Describe “With out Loading Dose” vs. “With Loading Dose”

A

With OUT:
- if you start with small dose it takes longer to get to TW & it can keep increasing to the TW

WITH:
- if you give higher dose to start, it gets to TW faster & stays within the TW range

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53
Q

Higher than TW =

A

problems with toxicity

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54
Q

Lower than TW =

A

problems with efficacy

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55
Q

Describe the frequency of drug dosing and plasma concentrations

A

24 hrs/dose
- has a larger range

8 hrs/dose
- range of plasma [ ] is lower

TW determines how much of dose you give

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56
Q

What is drug metabolism the study of? What is the definition & purpose?

A

Study of biotransformation

Definition: Metabolic breakdown of drugs by
living organisms via enzymatic alteration

Purpose: Facilitates elimination of drugs
- b/c don’t want them to continue circulating in system

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57
Q

What is metabolism?

A

Most drug metabolizing enzymes are hepatic (liver)

These enzymes may be inhibited or activated by drugs

Important for multi-drug use as one drug can affect the metabolism (and therefore the duration of action) of second drug

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58
Q

What is the most imp. site of drug metabolism?

A

LIVER

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59
Q

If liver function is impaired…

A

could lead to adverse drug reactions (b/c it is the most imp. site of drug metabolism)

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60
Q

What is metabolism’s 2 major categories?

A

Phase I and Phase 2 for a prodrug (admin. in inactive form & req’s metabolism to activate it) and active drugs (leads to inactivation through metabolism)

making drugs more readily excreted

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61
Q

What is the metabolism drug transformation?

A

lipophilic to hydrophilic
- more dissolved in water & therefore easier to eliminate

62
Q

What are the drug Metabolism Reactions?

A

Phase 1 Reactions
- Increase hydrophilicity (CYP enzymes)
◦ *Oxidation
◦ Reduction
◦ Hydrolysis

Phase 2 Reactions
- Further increase hydrophilicity (add conjugates to drug to make it more hydrophilic)
◦ Glucuronidation
◦ Acetylation
◦ Sulfation

63
Q

Phase 1 metabolism example

A

Hydrolysis
◦ OH group added

64
Q

Phase 2 metabolism examples

A

Glucuronidation
◦ Carboxylic acid, alcohol, phenol, amine

Acetylation
◦ Amines

Sulfation
◦ Alcohol, phenol, amine

65
Q

What are the therapeutic consequences of metabolism?

A

◦Accelerated renal excretion (or slowed)
◦Drug inactivation ◦Activation of prodrugs ◦Decreased toxicity ◦Increased therapeutic action

◦Increased toxicity

66
Q

What is meant by the 1st pass effect of metabolism?

A

Blood from the intestine goes to liver via the portal vein

From the liver, blood goes to the heart for circulation via the hepatic vein and vena cava

*Drugs absorbed from the intestine go to the liver first, then to rest of body

The liver contains many enzymes that metabolize a wide range of drugs (and natural compounds in the diet)

67
Q

Drugs absorbed from the intestine go to the ____ first, then to rest of body

A

liver

68
Q

What is bioavailability (in metabolism)?

A

A measurement of the RATE and EXTENT to which a drug reaches target site (e.g., receptor) of action

Bioavailability = AUC oral/AUC injected x 100

69
Q

What are factors affecting bioavailability?

A
  • the route
  • how quickly it’s metabolized
70
Q

What is the bioavailability for the following:
- IV
- IM
- Subcutaneous
- Oral
- Rectal
- Inhalation
- Transdermal
- Topical

A
  • IV
  • 100% –> rapid onset
  • IM
  • 75-100% –> may be painful
  • Subcutaneous
  • 75-100% –> may be painful, small volumes
  • Oral
  • 5-100% –> most convenient; subject to 1st pass effect
  • Rectal
  • 30- <100% –> less 1st pass effect than oral
  • Inhalation
  • 5-100% –> often very rapid onset
  • Transdermal
  • 80- <100% –> slow onset, prolonged duration
  • Topical
  • <5% –> absorption is not desired
71
Q

What are hepatic drug metabolizing enzymes?

A

ytochrome P450 (CYP) system
◦ Microsomal enzyme system
◦ Metabolize ~75% of drugs (majority)

18 CYP families, 44 subfamilies (in genome - classified by how similar they are)
◦ 57 functional human CYPs (encode hemoproteins)
◦ 58 non-functional (pseudogenes)

Only ~dozen CYPs involved in drug metabolism
◦ CYP1, CYP2 and CYP3 families

◦Name: spectral absorbance peak at 450 nm (reduced state, bound to CO)
◦Multi-gene family
◦ All organisms (arose 3 billion yrs ago)
◦Gene duplication and divergence
◦Active site: heme prosthetic group

72
Q

What is the active site for Cytochrome P450 (CYP) enzymes?

A

heme prosthetic group

73
Q

What is the most common CYP-related catalytic reactions?

A

Most common reaction is MONOOXYGENATION:

RH+O +2H+ +2e– →ROH+H O 22
*i.e., addition of oxygen atom to organic substrate (RH)

NAD(P)H-driven redox
◦NADPH-cytochrome P450 oxidoreductase (POR)

Protein structure of individual CYP related to substrate

(determine which drugs are metabolized b/c diff. sub’s have diff. drugs that they metabolize)

74
Q

What is the function of CYPs in humans?

A

Endogenous (synthesis) ◦ Steroids
◦ Cholesterol
◦Fatty acids

Exogenous (metabolism)
◦Environmental toxins/pollutants (e.g., cigarette smoke)
◦Drugs (activation/inactivation)

75
Q

Why do we study CYPs?

A

Important for key aspects in clinical pharmacology: ◦Metabolize ~75% of drugs
◦Drug interactions
◦Inter-individual variability in drug metabolism
◦ Predict toxic effects / non-response

76
Q

Where are CYPs found?

A

Highest tissue expression: Liver and gut wall
◦ CYP2D6 example figure above (GTEx data)

Cellular location: endoplasmic reticulum (microsomal), mitochondria

77
Q

Where is the highest tissue expression for CYPs?

A

Liver and gut wall
◦ CYP2D6 example figure above (GTEx data)

78
Q

Where is the cellular location of CYPs?

A

endoplasmic reticulum (microsomal), mitochondria

79
Q

What is the majority (most imp. family) of CYP isoforms that are clinically prescribed drug metabolized?

A

CYP3A 4/5

80
Q

Phase I

A

(oxidation, reduction, hydrolysis) Reactive or polar groups added
◦ Oxidation by CYPs

81
Q

Phase II

A

(conjugation)
Conjugated to polar compounds
◦ UDP-glucuronosyltransferases (UGTs)
◦ N-acetyltransferases (NATs)
◦ Glutathione S-transferases (GSTs)
◦ Sulfotransferases (SULTs)

82
Q

How do CYPs influence the activity of drugs?

A

Drug → metabolized by CYP → inactive metabolite
Prodrug (inactive)→ metabolized by CYP → active metabolite

↑ active metabolite can lead to drug toxicity
↓ active metabolite can lead to treatment non-response

Prodrug example: codeine (inactive) is converted into morphine (active), predominantly by CYP2D6

83
Q

↑ active metabolite can lead to _______

A

drug toxicity

84
Q

↓ active metabolite can lead to ________

A

treatment non-response

85
Q

What is a prodrug ex?

A

codeine (inactive) is converted into morphine (active), predominantly by CYP2D6

86
Q

Explain CYP nomenclature

A

Family
◦≥40% sequence homology
Subfamily
◦≥ 50% sequence homology

CYP 3 A 4 * 2
Superfamily
Family
Subfamily
Gene identifier / isoform
Allele

87
Q

Brief genetic recap

A

DNA gets transcripted to RNA and then translated to protein

88
Q

Describe the genetic variation & impact on protein function

A

SNP: small changes (subtle) can change the sequence
- modify it - but still will work just maybe not as effectively)

Deletion & Insertion: makes it nonsense (dramatic diff.)
- completely destroy function of enzymes

Individuals inherit one allele (variant of a gene) from each parent

89
Q

Human CYPs are…

A

highly polymorphic (i.e., large amounts of genetic variation)

Genetics can alter CYP activity
Alleles are annotated when a genetic variant has been documented that either:
◦ Changes protein sequence ◦ Changes protein function

90
Q

Changes in genetics affect…

A

metabolism capacity

  • can slow metabolism if in the drug toxicity range b/c can’t breakdown drug as effectively/fast
  • can ultra-rapid metabolism
  • metabolize it more quickly/breakdown
91
Q

Decreased drug metabolism leads to…

A

drug toxicity or failure to generate active drug from prodrug

92
Q

Most standard drug dosing is based on…

A

population means, representing normal metabolic status

93
Q

Increased drug metabolism leads to…

A

metabolism levels or subtherapeutic levels or toxicity due to more active drug from prodrug

94
Q

PK:

A

is the study of what the body does to a drug
◦ ADME are four essential PK processes

95
Q

Absorption:

A

Factors that influence absorption (route, PKa, etc.), un-ionized molecules pass through lipid membranes,

96
Q

Distribution:

A

Compartment models, Vd, loading dose

97
Q

Metabolism:

A

Phase I and Phase 2, CYP enzymes, as well as the influence of genetic factors

98
Q

What are non-genetic factors that influence CYP metabolism?

A

CYP metabolism can be altered in two directions: ◦Inhibition / Induction

Drug-drug interactions are clinically relevant
◦ Aging society and polypharmacy (chronic disease burden)

Other non-drug related factors:
◦ Age / Pregnancy / Disease / Diet / Pollutants
◦ e.g., diseases: hepatitis, cirrhosis, hemochromatosis

99
Q

What is CYP inhibition?

A

*Decrease in enzyme-related processes, enzyme production, or enzyme activity

Certain drugs inhibit certain CYPs
◦ Most not specific for only one CYP

Reversible or irreversible

Most common cause of drug-drug interactions

Can lead to PHENOCONVERSION
◦ Mismatch genetics (genotype) & actual drug metabolism capacity
- but inhibitors are making you into a poor metabolizer

100
Q

The allosteric site is the…

A

regulatory site

101
Q

The active site is the…

A

drug transformation

102
Q

Describe REVERSIBLE competitive inhibition

A

Substrates can differ in binding affinity

Can prevent this: changing concentrations of ligands can alter active site occupancy

103
Q

Describe REVERSIBLE NON-competitive inhibition

A

Inhibitor binds to allosteric site –> conformational changes –> blocks substrate

No direct competition

104
Q

IRREVERSIBLE Mechanism based inhibition

A

Inhibitor binds to active site –> stable intermediate-enzyme complex –> new enzyme required

(need to produce a new enzyme to get around it)

105
Q

Describe CYP induction

A

Certain drugs induce the expression of certain CYPs

CYP gene promoter - where the elements for gene expression bind
- turned on more & more gene expression is happening

CYP gene - mRNA - will be translated to protein

106
Q

What is Rifampin?

A

is an inducer of multiple CYP enzymes

107
Q

What does Rifampin do?

A

Antibiotic
◦Particularly used in tuberculosis treatment

Binds to nuclear receptor pregnane X receptor (PXR) ◦Heterodimer with the retinoic receptor (RXR)

STRONG/POTENT CYP2C19 and CYP3A inducer

MODERATE CYP2B6, CYP2C8, CYP2C9 inducer

108
Q

What are CYP3A4 inducers?

A

CYP3A metabolize the highest proportion of drugs (>30%)

109
Q

What are examples of CYP3A4 inducers?

A

Rifampin

Carbamazepine
◦ Anti-epileptic

St. John’s wort
◦ Herbal medicine
◦ Depression

110
Q

What are clinical implications of CYP induction? & what does it lead to?

A

Increased transcription → increased expression → increased CYP enzyme

Leads to enhanced drug metabolism and clearance
◦ Drug (↓ active metabolites, therapeutic failure)
◦ Prodrug (↑ active metabolites, toxicity)
- given in an inactive form
◦ Narrow therapeutic index drugs

111
Q

What is the CYP Interaction Table (Flockhart Table)?

A

Useful resource for curated CYP:
◦Substrates / Inhibitors / Inducers
◦ 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A

Drug interaction search function
◦Mobile app in development

(slide 96 & 97 has the definitions of it)

112
Q

Ticlopidine:

A

antiplatelet drug to prevent strokes (strong 2B6)

113
Q

Voriconazole:

A

◦ Antifungal azole
(moderate 2B6)
◦ strong inhibitor of CYP3A family

114
Q

What is the summary of CYPs and therapeutic
response?

A

Inhibitors, inducers and active/inactive metabolite levels for different types of drugs

Example is for when the theoretical CYP is the major determinant of metabolite concentrations

slide 100 & 101

115
Q

What are some key clinical implications: factors influencing CYP metabolism?

A

Avoid prescribing interacting drugs
◦ Alternate drugs when available (efficacy)
◦ Timing of medications

If genetic testing is unavailable, consider family history
◦ Clinical practice guidelines

Dose titration/monitoring clinical outcomes

116
Q

What is the main point of CYPs in drug metabolism?

A

Oxidation by the Cytochrome P450 monooxygenase system
◦ Key physiological and pharmacological functions

117
Q

What are the numerous factors affecting CYP biotransformation?

A

◦ Genetic influence
◦ Non-genetic (drug interactions: inhibition and induction, as well as other)
◦ Understanding this, can lead to better clinical outcomes – SAFER and MORE EFFECTIVE treatments

118
Q

Where is the primary (but not the only) site of drug metabolism?

A

LIVER

119
Q

Drugs are metabolized to more…

A

hydrophilic compounds
◦ Facilitates elimination by kidneys

120
Q

A _____ is a drug that is inactive until it is metabolized

A

pro-drug

121
Q

Phase 1 (CYP enzymes):

A

oxidation, reduction, hydrolysis

122
Q

Phase 2:

A

conjugation reactions
◦ glucuronidation(C H O -), sulfation(SO 2-), acetylation (C H O -)

123
Q

____ and ______ have important clinical implications

A

genetics

drug-drug interactions

124
Q

What is elimination?

A

Most drugs and drug metabolites are cleared from
the body by KIDNEYS, some are excreted in feces

Kidney function
◦ If impaired, this could lead to adverse drug effects

125
Q

Where are most drugs & drug metabolites cleared from the body by?

A

KIDNEYS, some are excreted in feces

126
Q

What is renal elimination?

A

Low molecular weight drugs enter kidney (via renal artery)
◦Lipid soluble drugs move back into blood
◦Non-lipid soluble, polar, and ionized drugs remain in urine

Creatinine clearance used to assess renal impairment

127
Q

What are the routes for elimination?

A

Kidney: filtration, secretion, reabsorption

Gastrointestinal tract: bile, feces

Lungs: volatile substances

Miscellaneous: saliva, sweat, tears, etc.

128
Q

What are the most common routes for drug elimination?

A

urine & feces
◦ Kidney function is affected by disease; may need to adjust drug dosage accordingly
◦ Urine pH can vary with diet; this may affect drug elimination – how?

129
Q

What is half-life?

A

Half-life (t1/2): The time it takes for HALF of the drug
to be removed from the body

Some drugs are removed quickly:
◦e.g., Fentanyl half life is about 1 hour
◦e.g., Diazepam half life is about 200 hours

130
Q

Apply the concept of half-life

A

*More than 95% of drug is cleared after 5 half-lives

Drug clearance is not linear

A given proportion of drug is cleared per unit time

131
Q

Where are most drugs eliminated by?

A

kidneys
◦ Kidney function can affect half-life and therefore toxicity

132
Q

Drug elimination is ______ with time

A

NOT linear

133
Q

Half-life:

A

the time required for 50% of drug to be metabolized or eliminated
◦ Five half-lives for >95% of drug to be metabolized or eliminated

134
Q

Steady state:

A

five half-lives required to reach steady state

135
Q

In summary, what are important factors that
contribute towards differences in response to medications?

A
  1. Genetics
  2. Ethnicity
  3. Sex
  4. Age
  5. Disease
  6. Drug interactions
136
Q

Describe the ethnicity factor & provide an example

A

Ancestry: ethnic origin/descent
◦ Moving away from race terminology
◦ Rough proxy for genetic factors (genetic testing preferred)
◦ Environmental factors (e.g., diet)

Examples:
◦ African-Americans increased risk of heart failure from HYDRALAZINE (treatment of high blood pressure)
◦ East Asian descent ALCOHOL metabolism (flushing and palpitations)

137
Q

Describe the sex and variation in drug response factor

A

Sex differences
◦ 8 of 10 withdrawn drugs effect women more than men
◦ Women underrepresented in the research pipeline
ex: body fat, liver, kidney’s, heart, & weight

Pregnancy
◦ Physiological changes
◦ Relevant for both the mother and fetus

138
Q

Describe the age and variation in drug response factor

A

Drug metabolism /elimination less efficient:
◦Newborns and the elderly

More side effects in vulnerable groups

Contributing factors
◦Body composition changes (fat and BMI)
◦ Polypharmacy

139
Q

What is the effect of age on drug response?

A

Renal Excretion
◦ Glomerular filtration rate (GFR) lower in neonates ◦GFR also declines from 20 years
◦Takes longer to excrete drugs

Drug metabolism
◦ Changes in enzyme expression levels (several enzymes low/not expressed in neonates)
◦CYPs and Phase II conjugating enzymes

140
Q

What is the importance of disease in drug response?

A

Disease of the major organs related to drug metabolism and excretion
◦Impairs these processes

Kidneys
◦Nephrotic syndrome

Liver
◦Hepatitis, cirrhosis, hemochromatosis

141
Q

Diseases can alter drug response through receptor or signal-transduction mechanisms:

A

Receptors
◦Myasthenia gravis (autoimmune condition, influences nACh receptors) – neuromuscular transmission drugs

Signal transduction
◦Hyperthyroidism, e.g., through thyroid adenomas, influence GPCR targeting therapeutics

142
Q

Describe drug interactions in drug response

A

Modification of the action of one drug by another

Drug-drug interactions are clinically relevant
◦ Aging society and polypharmacy (chronic disease burden)

Account for 5-20% ADRs (30% fatal ADRs)

Pharmacodynamic or pharmacokinetic interactions

143
Q

Pharmacodynamic example: warfarin

A

Warfarin (anticoagulant)
◦ Competes with vitamin K, inhibits coagulation factor synthesis

Antibiotics can ↓ vitamin K production ◦ Anticoagulation action of warfarin ↑
◦ Clinical implication: ↑ risk of bleeding

Drugs that ↑ bleeding risk (other mechanisms), ↑ warfarin bleeding risk
◦ e.g., aspirin and platelet thromboxane A 2 biosynthesis (stomach bleeding)

144
Q

Summarize pharmacokinetic interactions

A

Can be related to any ADME process, but very important to consider key drug metabolizing enzymes
◦ Cytochrome P450 (CYP) enzymes
◦ Involved inactivation/activation of drugs

CYP metabolism can be altered in two directions:
◦ Inhibition / Induction

145
Q

Key PK and PD considerations for differences in response to medications

A

Variability in the plasma free drug concentration ◦Different bioavailability (e.g., GI disease)
◦ Different binding to proteins and other chemicals
◦CYP enzymes (genetic differences, inhibition/induction)
◦Liver and kidney function

Variability of receptor sensitivity
◦Number of receptors present
◦Variation in effector pathways
◦Desensitization pathways

Another imp. factor: ADHERENCE
- if you’re not taking a medication, you’re not going to get an effect

146
Q

Bioavailability:

A

Fraction of unchanged drug in circulation

147
Q

Volume of distribution (Vd):

A

Apparent space in body available to contain the drug

148
Q

Drug half-life (t1/2):

A

Time to reduce the active substance of a drug by 50%

149
Q

Clearance (CL):

A

The ability of the body to eliminate the drug

150
Q

Pharmacokinetics / ADME summary:

A

Absorption: route of administration, bioavailability, pH
Distribution: volume of distribution, compartments
Metabolism: Phase I (CYPs) and Phase 2, first-pass effect, bioavailability, inducers, inhibitors
Elimination: drug half-life, clearance

PK and PD together provide a framework for understanding the time course of drug effect

Pharmacology (Fall) (28 decks)

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