Pharmacokinetics & Drug Metabolism Flashcards
(150 cards)
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
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
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)
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.)
5
Q
Why should you care about PK?
Enhance _____ and prevent/decrease _____
A
efficacy
toxicity
6
Q
What happens to a drug after it has been injected or swallowed?
A
Absorption, Distribution, Metabolism, Elimination
7
Q
What is ADME?
A
Absorption
Distribution
Metabolism
Elimination
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
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
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
11
Q
What are the routes of administration: absorption patterns?
A
◦Oral
◦IV
◦ Subcutaneous
◦ Intramuscular ◦Transdermal patch
◦ Rectal
◦ Inhalation
◦ Sublingual
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
13
Q
Where are ALKALINE drugs absorbed?
A
in the intestine
14
Q
What is the 1st pass metabolism?
A
some drugs are immediately metabolized in the liver
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
16
Q
What is a major player in absorption?
A
the small intestine
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
18
Q
Drug absorption requires…
A
drug permeation of cell membranes
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
20
Q
Only _____ molecules diffuse across lipid membranes
A
un-ionized
21
Q
At LOW pH, ___ drugs are un-ionized and ___ are ionized
A
ACIDS
bases
22
Q
pHgastric juice =
A
2.0
23
Q
pHsmall intestine =
A
5.3
24
Q
pHplasma =
A
7.4
25
What is pKa?
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
26
The lower the pKa, the more _____ the compound and the ______ the acid
ACIDIC
STRONGER
27
pKa:
pH when 50% of drug is ionized and 50% is not ionized
28
Video about stomach acid & drugs
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
29
Rate of drug absorption depends on numerous factors:
- Formulation
- Solubility (water/lipid)
- pKa
- Gastric pH
- GI motility
30
GI motility:
Food -->
Emotions, exercise (sympathetic nervous system) -->
Rest (parasympathetic nervous system) -->
Cold fluids -->
◦ Decreases gastric emptying
◦ Decreases gastric emptying
◦ Increases gastric emptying
◦ Increases gastric emptying
31
Describe the inhalational barrier of absorption
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
32
What are the factors influencing absorption in the lungs?
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
33
Most drugs are absorbed by _____ _____
passive diffusion
34
______ drugs have greater passive diffusion than charged drugs
UN-ionized
35
For drugs absorbed in the intestine, _____ ____ speeds up absorption
gastric emptying
36
Describe Distribution
◦ 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
37
What is Volume of Distribution (Vd)?
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.
38
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
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)
39
High Vd:
drug has higher concentrations in extravascular tissue compared to vascular compartment (not homogenous distribution)
40
Describe the Distribution: hypothetical models
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 [ ]
41
One-Compartment Model of Drug Disposition is the...
most commonly used model in clinical practice
- b/c it's convenient
42
Why use compartment
models?
To PREDICT THE CONCENTRATION of a drug at any given time in any given body fluid or tissue
43
What is the Two-compartment model?
IV administration --> central and/or peripheral --> elimination
- some drugs do not distribute instantaneously to all parts of body
44
What is the Multi compartment models?
◦A single compartment model is the least accurate
◦Adding more compartments may not necessarily improve the predictive value
◦All models have limitations
45
What are factors influencing drug distribution in the body?
Examples include:
1. pKa of drug and pH of tissue compartment
- b/c diff. tissue compartments differ in their pH
2. Drug binding
3. Specialized distribution barriers
46
Describe Specialized distribution barriers
1) Placental barrier
- in pregnant woman
2) Blood-brain barrier (BBB)
- in everyone
47
What does Vd indicate?
Vd indicates whether a drug accesses all body water or is
limited to blood
48
What affects Vd?
Size, charge, protein binding all affect Vd
49
Lipophilicity ___ passive diffusion of drug across barriers
↑
◦ e.g., blood-brain barrier, placenta
50
Some drugs are ____ in body compartments
stored
◦ e.g., fat, bone
51
Loading dose =
Vd x desired plasma concentration
52
Describe "With out Loading Dose" vs. "With Loading Dose"
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
53
Higher than TW =
problems with toxicity
54
Lower than TW =
problems with efficacy
55
Describe the frequency of drug dosing and plasma concentrations
24 hrs/dose
- has a larger range
8 hrs/dose
- range of plasma [ ] is lower
TW determines how much of dose you give
56
What is drug metabolism the study of? What is the definition & purpose?
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
57
What is metabolism?
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
58
What is the most imp. site of drug metabolism?
LIVER
59
If liver function is impaired...
could lead to adverse drug reactions (b/c it is the most imp. site of drug metabolism)
60
What is metabolism's 2 major categories?
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
61
What is the metabolism drug transformation?
lipophilic to hydrophilic
- more dissolved in water & therefore easier to eliminate
62
What are the drug Metabolism Reactions?
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
Phase 1 metabolism example
Hydrolysis
◦ OH group added
64
Phase 2 metabolism examples
Glucuronidation
◦ Carboxylic acid, alcohol, phenol, amine
Acetylation
◦ Amines
Sulfation
◦ Alcohol, phenol, amine
65
What are the therapeutic consequences of metabolism?
◦Accelerated renal excretion (or slowed)
◦Drug inactivation ◦Activation of prodrugs ◦Decreased toxicity ◦Increased therapeutic action
◦Increased toxicity
66
What is meant by the 1st pass effect of metabolism?
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
Drugs absorbed from the intestine go to the ____ first, then to rest of body
liver
68
What is bioavailability (in metabolism)?
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
What are factors affecting bioavailability?
- the route
- how quickly it's metabolized
70
What is the bioavailability for the following:
- IV
- IM
- Subcutaneous
- Oral
- Rectal
- Inhalation
- Transdermal
- Topical
- 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
What are hepatic drug metabolizing enzymes?
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
What is the active site for Cytochrome P450 (CYP) enzymes?
heme prosthetic group
73
What is the most common CYP-related catalytic reactions?
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
What is the function of CYPs in humans?
Endogenous (synthesis) ◦ Steroids
◦ Cholesterol
◦Fatty acids
Exogenous (metabolism)
◦Environmental toxins/pollutants (e.g., cigarette smoke)
◦Drugs (activation/inactivation)
75
Why do we study CYPs?
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
Where are CYPs found?
Highest tissue expression: Liver and gut wall
◦ CYP2D6 example figure above (GTEx data)
Cellular location: endoplasmic reticulum (microsomal), mitochondria
77
Where is the highest tissue expression for CYPs?
Liver and gut wall
◦ CYP2D6 example figure above (GTEx data)
78
Where is the cellular location of CYPs?
endoplasmic reticulum (microsomal), mitochondria
79
What is the majority (most imp. family) of CYP isoforms that are clinically prescribed drug metabolized?
CYP3A 4/5
80
Phase I
(oxidation, reduction, hydrolysis) Reactive or polar groups added
◦ Oxidation by CYPs
81
Phase II
(conjugation)
Conjugated to polar compounds
◦ UDP-glucuronosyltransferases (UGTs)
◦ N-acetyltransferases (NATs)
◦ Glutathione S-transferases (GSTs)
◦ Sulfotransferases (SULTs)
82
How do CYPs influence the activity of drugs?
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
↑ active metabolite can lead to _______
drug toxicity
84
↓ active metabolite can lead to ________
treatment non-response
85
What is a prodrug ex?
codeine (inactive) is converted into morphine (active), predominantly by CYP2D6
86
Explain CYP nomenclature
Family
◦≥40% sequence homology
Subfamily
◦≥ 50% sequence homology
CYP 3 A 4 * 2
Superfamily
Family
Subfamily
Gene identifier / isoform
Allele
87
Brief genetic recap
DNA gets transcripted to RNA and then translated to protein
88
Describe the genetic variation & impact on protein function
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
Human CYPs are...
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
Changes in genetics affect...
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
Decreased drug metabolism leads to...
drug toxicity or failure to generate active drug from prodrug
92
Most standard drug dosing is based on...
population means, representing normal metabolic status
93
Increased drug metabolism leads to...
metabolism levels or subtherapeutic levels or toxicity due to more active drug from prodrug
94
PK:
is the study of what the body does to a drug
◦ ADME are four essential PK processes
95
Absorption:
Factors that influence absorption (route, PKa, etc.), un-ionized molecules pass through lipid membranes,
96
Distribution:
Compartment models, Vd, loading dose
97
Metabolism:
Phase I and Phase 2, CYP enzymes, as well as the influence of genetic factors
98
What are non-genetic factors that influence CYP metabolism?
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
What is CYP inhibition?
*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
The allosteric site is the...
regulatory site
101
The active site is the...
drug transformation
102
Describe REVERSIBLE competitive inhibition
Substrates can differ in binding affinity
Can prevent this: changing concentrations of ligands can alter active site occupancy
103
Describe REVERSIBLE NON-competitive inhibition
Inhibitor binds to allosteric site --> conformational changes --> blocks substrate
No direct competition
104
IRREVERSIBLE Mechanism based inhibition
Inhibitor binds to active site --> stable intermediate-enzyme complex --> new enzyme required
(need to produce a new enzyme to get around it)
105
Describe CYP induction
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
What is Rifampin?
is an inducer of multiple CYP enzymes
107
What does Rifampin do?
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
What are CYP3A4 inducers?
CYP3A metabolize the highest proportion of drugs (>30%)
109
What are examples of CYP3A4 inducers?
Rifampin
Carbamazepine
◦ Anti-epileptic
St. John’s wort
◦ Herbal medicine
◦ Depression
110
What are clinical implications of CYP induction? & what does it lead to?
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
What is the CYP Interaction Table (Flockhart Table)?
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
Ticlopidine:
antiplatelet drug to prevent strokes (strong 2B6)
113
Voriconazole:
◦ Antifungal azole
(moderate 2B6)
◦ strong inhibitor of CYP3A family
114
What is the summary of CYPs and therapeutic
response?
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
What are some key clinical implications: factors influencing CYP metabolism?
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
What is the main point of CYPs in drug metabolism?
Oxidation by the Cytochrome P450 monooxygenase system
◦ Key physiological and pharmacological functions
117
What are the numerous factors affecting CYP biotransformation?
◦ 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
Where is the primary (but not the only) site of drug metabolism?
LIVER
119
Drugs are metabolized to more...
hydrophilic compounds
◦ Facilitates elimination by kidneys
120
A _____ is a drug that is inactive until it is metabolized
pro-drug
121
Phase 1 (CYP enzymes):
oxidation, reduction, hydrolysis
122
Phase 2:
conjugation reactions
◦ glucuronidation(C H O -), sulfation(SO 2-), acetylation (C H O -)
123
____ and ______ have important clinical implications
genetics
drug-drug interactions
124
What is elimination?
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
Where are most drugs & drug metabolites cleared from the body by?
KIDNEYS, some are excreted in feces
126
What is renal elimination?
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
What are the routes for elimination?
Kidney: filtration, secretion, reabsorption
Gastrointestinal tract: bile, feces
Lungs: volatile substances
Miscellaneous: saliva, sweat, tears, etc.
128
What are the most common routes for drug elimination?
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
What is half-life?
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
Apply the concept of half-life
*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
Where are most drugs eliminated by?
kidneys
◦ Kidney function can affect half-life and therefore toxicity
132
Drug elimination is ______ with time
NOT linear
133
Half-life:
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
Steady state:
five half-lives required to reach steady state
135
In summary, what are important factors that
contribute towards differences in response to medications?
1. Genetics
2. Ethnicity
3. Sex
4. Age
5. Disease
6. Drug interactions
136
Describe the ethnicity factor & provide an example
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
Describe the sex and variation in drug response factor
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
Describe the age and variation in drug response factor
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
What is the effect of age on drug response?
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
What is the importance of disease in drug response?
Disease of the major organs related to drug metabolism and excretion
◦Impairs these processes
Kidneys
◦Nephrotic syndrome
Liver
◦Hepatitis, cirrhosis, hemochromatosis
141
Diseases can alter drug response through receptor or signal-transduction mechanisms:
Receptors
◦Myasthenia gravis (autoimmune condition, influences nACh receptors) – neuromuscular transmission drugs
Signal transduction
◦Hyperthyroidism, e.g., through thyroid adenomas, influence GPCR targeting therapeutics
142
Describe drug interactions in drug response
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
Pharmacodynamic example: warfarin
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
Summarize pharmacokinetic interactions
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
Key PK and PD considerations for differences in response to medications
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
Bioavailability:
Fraction of unchanged drug in circulation
147
Volume of distribution (Vd):
Apparent space in body available to contain the drug
148
Drug half-life (t1/2):
Time to reduce the active substance of a drug by 50%
149
Clearance (CL):
The ability of the body to eliminate the drug
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Pharmacokinetics / ADME summary:
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
