Pharmacokinetics/genomics Flashcards
1
Q
What is pharmacokinetics?
A
The study of how the body affects a drug through absorption, distribution, metabolism, and elimination
Pharmacokinetics determines the concentration of drug in plasma and at the drug target, how rapidly the drug will reach the target, and how long the drug will remain at the target.
2
Q
Name 4 things that determine Pharmacokinetics?
A
*the concentration of drug in plasama and at drug target
The chemical properties of the drug (molecular structure)
* The drug’s ability to move between different compartments
* The body’s ability to metabolize and excrete the drug.
These factors influence how a drug is absorbed, distributed, metabolized, and eliminated in the body.
3
Q
name the principles of ADME:
A
absorption- how will it get in
distribution- where will ig to
metabolism- how is it broken down
excretion- how does it leave
4
Q
What is absorption in pharmacokinetics?
A
The movement of drugs from its site of administration into the central compartment (plasma)
Absorption is essential for drugs to reach their target site and exert therapeutic effects.
5
Q
True/False: in most cases, the drug must go back to the central compartment first before it is metabolized and excreted
A
true
6
Q
How do IV medications differ in absorption?
A
IV medications are injected directly into the central compartment and bypass the absorption step
This allows for immediate availability in the bloodstream.
7
Q
What must a drug do before reaching its site of action?
A
Enter the plasma (central compartment) first before being metabolized and excreted
This is crucial for the drug to eventually exert its effects at the target site.
8
Q
fora drug to be absorbed it must ____ a membrane
A
permeate
Permeation can occur through passive diffusion, cell endocytosis, or using protein channels.
9
Q
What does Fick’s Law of Diffusion describe?
A
The passive flux of molecules down a concentration gradient
This law states that molecules move from high concentration to low concentration due to Brownian motion.
10
Q
If the distance separating the two regions (how thick it is) increases, what happens to diffusion?
A
it decreases
11
Q
What factors influence permeation?
A
- Molecular size, shape, and structural features
- Degree of ionization
- Relative lipid solubility of its ionized and nonionized forms
- Binding to serum and tissue proteins
- Lipid:water partition coefficient
These properties determine how well a drug can permeate membranes.
12
Q
name the three types of passive transport:
A
paracellular transport
diffusion
facilitiated diffusion
13
Q
What is the role of the plasma membrane in drug permeation?
A
It acts as a basic barrier that is selectively permeable
The plasma membrane allows certain substances to pass while restricting others.
14
Q
What are the methods of drug permeation?
A
- Passive diffusion
- Facilitated diffusion
- Active transport
- Paracellular transport
- Endocytosis/Exocytosis
These methods describe how drugs can enter or exit cells.
15
Q
What properties of the membrane affect permeation?
A
- Surface area
- Cell-cell junctions (tight)
- Thickness
- Presence of pore/channel
These factors can enhance or restrict the movement of drugs across the membrane.
16
Q
Fill in the blank: The ability of a drug to permeate membranes is influenced by its _______.
A
[molecular size, shape, degree of ionization, lipid solubility]
These properties are critical for determining how effectively a drug can be absorbed.
17
Q
True or False: The concentration gradient does not affect drug permeation.
A
False
A concentration gradient is essential for the passive diffusion of drugs.
18
Q
What is the Blood Brain Barrier (BBB)?
A
A selective permeability barrier that protects the brain from potentially harmful substances in the blood.
19
Q
What can disrupt the integrity of the BBB?
A
Inflammation can disrupt the integrity of BBB, allowing normally impermeant substances to enter the brain.
20
Q
In which parts of the CNS is the BBB leaky?
A
In some parts of the CNS, such as the brainstem.
21
Q
What factors can affect drug absorption?
A
- Drug-drug interactions
- Gut content
- GI motility (e.g. Gastroparesis)
- Splanchnic blood flow
22
Q
True false: IV drugs are 100% bioavailabe?
A
yes true that
23
Q
Define bioavailability.
A
The fractional extent to which an administered dose of a drug reaches its site of action or a biological fluid from which the drug has access to its site of action.
24
Q
What happens to a drug absorbed from the GIT before entering systemic circulation?
A
It first passes through the liver (portal circulation) where metabolism and biliary excretion may occur.
25
What is first-pass elimination?
Less than all of the administered dose may reach systemic circulation, resulting in reduced bioavailability.
26
What is the bioavailability of IV medications?
Bioavailability of IV medications is 100%.
27
a proton donor is a/an ____
a proton acceptor is a/an____
acid
base
28
What is pKa?
A dissociation constant that is the pH at which the molecule is 50% ionized and 50% non-ionized.
29
What is the difference between nonionized and ionized drugs?
* Nonionized drugs: high lipid solubility, hydrophobic, uncharged
* Ionized drugs: reduced ability to permeate membranes, hydrophilic, charged
30
which side is acidic and which is basic?
31
What determines the degree of ionization of a drug?
* Whether the drug is an acid or a base
* pH of the aqueous solution
* pKa of the drug
32
What do weak acids and weak bases try to achieve?
They try to reach equilibrium by donating or accepting protons.
33
What is the relationship between pH and hydrogen ion concentration?
pH = negative log of hydrogen ion (H+) concentration.
34
What types of molecules are most weak bases?
Most bases are amine-containing molecules (nitrogen).
35
What is a quaternary amine?
A permanently charged amine that does not cross barriers.
36
which is charged: a tertiary or quaternary amine?
a quaternary amine is charged, tertiary is NOT
37
how would you determine what kind of amine a structure is?
you would count the number of carbons attached to the nitrogen
| ex: 1 carbon attached = primary amine, 2 carbons = secondary
38
List examples of weak acids.
* Barbiturates
* Propofol
* Opioids
* Acetaminophen
* Aspirin
39
List examples of weak bases.
*opioids
* Local anesthetics
* Benzodiazepines
* Vasopressors
40
What is the pH difference between fetal blood and maternal blood?
Fetal blood is more acidic than maternal blood
## Footnote
This difference in pH affects various physiological processes.
41
also known as the reverse log of dissociation constant
pKa
42
the pH in which 50% of the drug is ionized and 50% is nonionzed is known as :
pKA
43
the lower the pH relative to pKa, the ___ the amount of drug in pronated form
greater
44
molecules that can move thru membranes are nonionized, but once it moves over to a new compartment with a different pH, it can change to the ionized form. This is known as:
ion trapping
45
Which is more acidic: the stomach or the intestine?
The stomach is more acidic than the intestine
## Footnote
This acidity plays a role in digestion and absorption.
46
What is ion trapping?
Ion trapping occurs when molecules change to an ionized form in a new compartment with a different pH
## Footnote
This affects drug absorption and distribution.
47
What is the pKa of aspirin?
The pKa of aspirin is 2.97
## Footnote
This property affects aspirin's absorption in the stomach versus the intestines.
48
What factors affect drug distribution from the central compartment to the peripheral compartment?
Factors include:
* Cardiac output
* Regional blood flow
* Protein binding
* Lipid solubility
* Degree of ionization
* Molecular weight
## Footnote
These factors influence how effectively a drug reaches its target tissues.
49
What are the main components of blood involved in drug binding?
Main components include:
* Albumin
* ⍺1-acid glycoprotein
* RBCs
## Footnote
These components affect the availability of drugs in the bloodstream.
50
What is the effect of capillary permeability on drug distribution?
Capillary permeability affects the rate of delivery and amount of drug distributed into tissues
## Footnote
This can vary greatly between different organs.
51
Which organs are considered well-perfused and receive drugs first?
Well-perfused organs include:
* Liver
* Kidney
* Brain
* Heart
## Footnote
These organs receive drugs within seconds due to their high blood flow.
52
What is redistribution in pharmacokinetics?
Redistribution refers to drug movement from vessel-rich groups to vessel-poor groups (e.g., fat)
## Footnote
This process can lead to the initial loss of clinical effect of anesthetic drugs.
53
What is the formula for Volume of Distribution (Vd)?
Vd = Total amount of drug in the body / Amount of drug in the plasma
## Footnote
This is a key concept in understanding drug distribution.
54
What does a high volume of distribution indicate?
A high volume of distribution indicates a greater amount of drug is found in extravascular versus vascular compartments
## Footnote
This suggests extensive distribution into body tissues.
55
what does a low volume of distrubtion equal to:
high vascular vs extravascular
56
if a drug is highly lipid soluble, what would be the volume of distrubtion?
HIGH
57
What is the difference between one compartment and two compartment models?
One compartment assumes homogenous distribution, while two compartments differentiate between central and peripheral compartments
## Footnote
This affects the accuracy of pharmacokinetic predictions.
58
What characterizes a three compartment model?
A three compartment model discriminates between central compartment, fast-distributing tissues, and slow-distributing tissues
## Footnote
This model provides the most accurate representation of drug behavior in the body.
59
What is considered the central compartment in pharmacokinetics?
The central compartment includes blood/plasma, great vessels, heart, and lungs
## Footnote
Initial drug distribution occurs primarily in this compartment after bolus injection.
60
What drugs have a significant first-pass pulmonary uptake?
Drugs with > 65% first-pass pulmonary uptake include:
* Lidocaine
* Propofol
* Fentanyl
* Sufentanil
## Footnote
This property affects their overall bioavailability.
61
What are highly hydrophilic drugs characterized by?
Little tissue penetrance
## Footnote
These drugs do not easily cross cell membranes and are typically confined to the bloodstream.
62
What are the two phases of the Two Compartment Model?
Rapid initial distribution, slow late elimination
## Footnote
This model helps describe how drugs distribute in the body and their subsequent elimination.
63
What are the two phases of drug leaving the central compartment?
Alpha Distribution, Beta Elimination
## Footnote
Alpha phase involves initial distribution from plasma to tissues, while beta phase involves drug removal from plasma.
64
What is characterized by a steep slope in the plasma concentration curve?
Alpha Distribution
## Footnote
This phase is typically seen with highly lipid-soluble drugs.
65
What is the definition of the Beta Elimination phase?
Tissue back to plasma; drug removed from plasma by metabolism and elimination
## Footnote
This phase shows a flatter curve indicating irreversible elimination.
66
What are the three compartments in the Three Compartment Model?
Blood, lean tissue, fat
## Footnote
This model is most applicable to anesthetics and includes rapid distribution, slower redistribution, and terminal elimination.
67
What are the three phases of drug distribution in the Three Compartment Model?
Alpha, Beta, Gamma
## Footnote
Alpha is rapid distribution, Beta is slower redistribution, and Gamma is terminal elimination.
68
Name the characteristics of a drug that has a large Vd
they are unbound
lipid soluble
fast onset
low plasma concentration, slower elminination
| ex: prop, fent, iso
69
name the characteristics of a drug that has a small Vd
highly protein bound
low lipid solubility
slow onset
high degree of ionization
| ex: NMBA, warfarin, ketoralac
70
What is Half-Time vs. Half-Life (T1/2)?
Half-time: 50% removed from plasma; Half-life: 50% removed from body
## Footnote
These terms are used interchangeably, though they refer to slightly different concepts.
71
What defines a drug as 'eliminated' from the body?
When 96% of drug is removed, equivalent to 4-5 Half-lives
## Footnote
This is a common threshold used in pharmacokinetics.
72
at a constant rate of clearance, a drug with a high Vd will have a ________ than a drug with lower Vd
longer elimination half life
73
What is meant by Steady State in pharmacokinetics?
Stable Plasma Concentration of Drug
## Footnote
This occurs when all body compartments have equilibrated and the amount of drug in plasma has reached therapeutic levels.
74
How many half-lives does it take to approach steady state?
4-5 half-lives
## Footnote
This is important for drug dosing and administration strategies.
75
What factors can affect drug distribution in the body?
Age, Obesity, Liver/kidney disease, Hypovolemia
## Footnote
These factors can significantly alter pharmacokinetics.
76
Fill in the blank: A drug with a high Vd will have a longer _______ than a drug with lower Vd.
elimination half-life
## Footnote
This indicates the relationship between volume of distribution and drug clearance.
77
What are xenobiotics?
Substances foreign to the body such as diet, environmental contaminants, and cosmetic products
## Footnote
Examples include plants, processed foods, and additives.
78
What is the primary goal of metabolizing xenobiotics?
Convert hydrophobic chemicals into hydrophilic derivatives for easier elimination from the body through urine or bile
## Footnote
Also aims to terminate biological activity of the drug.
79
Fill inthe blank: Most xeobiotics are ___ chemicals
lipophilic
80
What are the two phases of drug metabolism?
Phase 1: Biotransformation
Phase 2: Synthesis
81
what 3 things occur in a phase 1 biotransformation reaction
oxidation
reduction
and hydrolysis
82
83
What is the role of cytochrome P450 enzymes in drug metabolism?
Involved in Phase 1 reactions, metabolizing diverse compounds to increase hydrophilicity
## Footnote
CYPs are embedded in the phospholipid bilayer of the ER.
84
What are the characteristics of Phase 1 reactions?
Biotransformation through oxidation, reduction, and hydrolysis; inactivation of drugs (except prodrugs)
## Footnote
Functional groups added include -OH, -COOH, -SH, -O-, NH2.
85
What is a prodrug?
An inactive drug that is converted into an active drug within the body
## Footnote
Prodrugs are stable for storage and better at permeating membranes.
86
What can lead to interindividual differences in drug metabolism?
Genetic polymorphisms and environmental exposure
## Footnote
CYP expression can vary significantly among individuals.
87
Fill in the blank: The addition of H2O to an ester or amide to break a bond is known as _______.
Hydrolysis
88
What are the effects of drug-drug interactions?
Inhibition of metabolism of one or both drugs, leading to elevated plasma levels and potential toxicities
## Footnote
Example: Grapefruit juice inhibits intestinal CYP3A4.
89
What is the function of Phase 2 reactions?
Conjugation of Phase 1 products with a second molecule to increase water solubility for elimination
## Footnote
Transferases are primarily responsible for this process.
90
What is Hofmann elimination?
A spontaneous reaction not dependent on kidney or liver, influenced by pH and temperature
## Footnote
Example: Cisatracurium/Nimbex undergoes Hofmann elimination.
91
True or False: Active metabolites of drugs always have weaker biological activity than the parent compound.
False
## Footnote
Active metabolites can sometimes have stronger activity and can accumulate to toxic levels.
92
What are the organs with drug-metabolizing capacity?
GI Tract, Liver, Kidneys, Lungs
## Footnote
Each organ plays a role in different aspects of drug metabolism.
93
What is the impact of CYP inducers?
Increase the metabolism of other drugs, decreasing plasma levels and potentially leading to loss of efficacy
## Footnote
Examples include alcohol, antiepileptics, and smoking.
94
What is the significance of gut bacteria in drug metabolism?
Gut bacteria can influence the composition of gut flora, affecting metabolism and the first-pass effect
## Footnote
They play a role in the metabolic clearing process.
95
Fill in the blank: Phase 1 enzymes are known as _______ and include examples like CYP3A4.
Oxidases
96
What is the characteristic of First Order Kinetics?
Constant fraction (%) of drug is metabolized per unit time
## Footnote
Clearance is proportional to the concentration of drug in the system.
97
How does plasma concentration affect metabolism in First Order Kinetics?
Higher the plasma concentration = higher rate of metabolism
98
Is elimination in First Order Kinetics saturable?
No, elimination is not saturable
99
Is First Order Kinetics dose dependent?
No, it is dose independent
100
What does the half-life indicate in First Order Kinetics?
Amount of time to decrease plasma concentration of drug by 50% is the same regardless of initial concentration
101
What is the characteristic of Zero Order Kinetics?
Constant amount of drug metabolized per unit time (e.g., 2 mg/unit time)
102
How does clearance vary in Zero Order Kinetics?
Clearance will vary depending on concentration of drug that is achieved
103
What happens to drug elimination pathways in Zero Order Kinetics?
They become saturated at high doses
104
What is an example of a drug that follows Zero Order Kinetics?
Aspirin, alcohol, phenytoin, heparin, warfarin, theophylline
105
What are the routes of elimination?
* Renal: Urine
* Hepatic: Biliary/Fecal
* Other: Lungs, Breast Milk, Sweat, tears, Saliva, Skin, hair
106
What factors affect renal clearance?
* Protein binding
* GFR
* Renal blood flow
107
What type of compounds excrete easier in renal clearance?
Polar/charged compounds
108
What factors are involved in Biliary (Hepatic) Clearance?
* Blood Flow to Liver (Perfusion Dependent)
* Hepatic Extraction Ratio (Capacity Dependent)
109
What does an Extraction Ratio of 1.0 indicate?
100% of drug delivered to liver is removed
110
fraction of drug removed from the blood during one pass of the liver
extraction ratio
111
What does an Extraction Ratio of 0.5 indicate?
50% of drug delivered to liver is removed
112
What determines perfusion dependent elimination?
Amount of blood flow to liver
113
How does hepatic blood flow affect drug clearance?
* Reduced hepatic blood flow = decreased drug clearance
* Increased liver blood flow = increased drug clearance
114
What is Capacity Dependent Elimination?
The ability of the liver to extract drug from the blood, limited by capacity of hepatic enzymes
115
What happens to drugs with high extraction ratios?
They are rapidly cleared from blood
116
What are examples of drugs with high extraction ratios?
* Fentanyl
* Sufentanil
* Morphine
* Ketamine
* Propofol
* Bupivacaine
* Lidocaine
* Verapamil
* Diltiazem
* Metoprolol (ER > 0.7)
117
What characterizes drugs with low extraction ratios?
They are not efficiently cleared; only a small fraction of drug is eliminated from blood per unit time
118
What can cause changes to the Extraction Ratio?
Enzyme induction or inhibition, changes in protein binding
119
What is a significant component of patient-to-patient variability in drug response?
Genetic modifications in metabolic enzymes, interactions with other drugs, disease in the liver, kidneys or other organs of metabolism, age.
## Footnote
Age factors include young and old patients.
120
What are the expected effects of age on drug response in elderly patients?
Slower induction, decreased dose, longer wake-ups, more adverse reactions.
## Footnote
These effects necessitate careful monitoring and dosage adjustments.
121
What is a key characteristic of drug metabolism in neonates?
Metabolic enzymes are not fully mature, with microsomal enzymes developing over 6-12 months.
## Footnote
Neonates also have a much higher body water content compared to adults (90% vs. 60-70%).
122
What factors contribute to genetic variation in drug response?
Drug-metabolizing enzymes, drug transport molecules, molecular drug targets, gene dysregulation in disease.
## Footnote
These variations can significantly affect drug efficacy and safety.
123
What are epigenetic changes and their influences?
Changes such as histone modification that affect translation, influenced by environmental factors like diet, exposure to pathogens or pollutants, and age.
## Footnote
Epigenetic changes can impact gene expression without altering the DNA sequence.
124
What are polymorphisms in the context of pharmacogenomics?
Variants occurring at a frequency greater than 1% of the population, including single-nucleotide polymorphisms (SNPs), insertions, and deletions.
## Footnote
These can lead to changes in protein structure and function.
125
How does sex affect drug metabolism?
Women tend to have more rapid clearance of drugs metabolized by CYP3A4, resulting in decreased plasma levels and quicker emergence.
## Footnote
This may enhance awareness and recall in female patients.
126
What is the impact of ethnicity on drug metabolism?
Ethnicity can influence metabolism; for example, Asians may be poor metabolizers of opioids.
## Footnote
Genetic variations within different ethnic groups can affect drug response.
127
What is Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD)?
An X-linked trait affecting RBCs that leads to reduced glutathione levels and inability to protect RBCs from oxidative damage.
## Footnote
This deficiency can result in severe hemolytic anemia after ingestion of certain foods or drugs.
128
What are some signs and symptoms of G6PD deficiency?
Cyanosis, extremely low hemoglobin, headache, fatigue, tachycardia, dyspnea, lethargy, abdominal pain, splenomegaly, jaundice.
## Footnote
These symptoms arise from oxidative stress and hemolysis of red blood cells.
129
What types of drugs should be avoided in patients with G6PD deficiency?
Drugs that induce methemoglobinemia, such as benzocaine.
## Footnote
While anesthetics inhibit G6PD in vitro, there have been no documented cases of hemolytic crisis in vivo.
130
What is the initial management for hemolysis in G6PD deficiency?
Removal of offending hemolytic agent
## Footnote
Spontaneous recovery in 8-10 days but may need blood transfusion if acutely decompensating.
131
What is Acute Intermittent Porphyria (AIP)?
Autosomal dominant inherited metabolic disorder
## Footnote
Characterized by defects in heme synthesis and accumulation of precursors.
132
List the acute symptoms of Acute Intermittent Porphyria.
* Neurological symptoms (seizures, psychosis, weakness)
* GI symptoms
* Anxiety
* Confusion
* Autonomic instability (HTN, tachycardia)
* Emesis
* Severe abdominal pain
133
What are common triggers for Acute Intermittent Porphyria?
* Stress
* Fasting
* Dehydration
* Sepsis
* Drugs
134
What medications should be avoided in Acute Intermittent Porphyria?
* Barbiturates
* Diazepam
* Ketorolac
* Phenytoin
* Sulfa drugs
* Birth control pills
135
What anesthetic agents are considered safe for Acute Intermittent Porphyria?
* Propofol
* Midazolam
* Fentanyl
* Neuromuscular blockers
* Glycopyrolate/atropine
* Regional anesthesia
* Sevoflurane
* Nitrous oxide
136
What is the definition of Long QT Syndrome?
Prolonged QT interval > 450 ms in males, > 460 ms in females
## Footnote
This can lead to polymorphic ventricular tachyarrhythmias.
137
What causes congenital Long QT Syndrome?
Mutations to potassium, sodium, or calcium channels
138
What are the treatment options for Long QT Syndrome?
* Beta-blockers
* Limited exercise
* Automated implantable cardioverter-defibrillator (AICD)
139
What factors can prolong the QT interval?
* Dexamethasone
* Increased sympathetic activity (Epinephrine, Ketamine)
* Extreme bradycardia (anticholinesterases)
* Succinylcholine
* Anticholinergics
* Ondansetron/Zofran
140
Atypical psuedocholinesterases usually metabolize what % of a dose before reaching the NMJ?
90-95%
141
What is Malignant Hyperthermia?
Inherited skeletal muscle disorder characterized by muscle rigidity and hypermetabolic state
## Footnote
Caused by mutations to Ryanodine receptor (RyR1).
142
List the main triggers of Malignant Hyperthermia.
* Succinylcholine
* Volatile anesthetics
143
What are the signs and symptoms of Malignant Hyperthermia?
* Tachycardia
* Rapid increase in ETCO2
* Muscle rigidity (masseter spasm)
* Mixed respiratory and metabolic acidosis
* Increased body temperature (late)
* Myoglobinuria leading to renal failure
* Hyperkalemia leading to cardiac arrest
144
What is the first step in the treatment of Malignant Hyperthermia?
Discontinue the triggering agent
## Footnote
Followed by administration of Dantrolene.
145
What is the initial dose of Dantrolene for Malignant Hyperthermia?
2.5 mg/kg IV
## Footnote
Repeat every 5 minutes until symptoms decrease.
146
What is the purpose of the Caffeine Halothane Contracture Test?
To diagnose Malignant Hyperthermia
## Footnote
It is done via muscle biopsy.
