Exam 1 Flashcards
ADME, Pharmacogenomics
1
Q
What is pharmacology?
A
The study of the properties of drugs and their interactions with the living system.
2
Q
What is pharmacodynamics?
A
“What drugs do to the body”. Relationship between drug concentration and biologic effects with time.
3
Q
What is pharmacokinetics?
A
“What the body does to the drug”. The absorption, distribution, metabolism, and excretion of the drug.
4
Q
Explain dosing in relation to the bell curve.
A
Dosing of a drug was given to represent the 68% of people within 1 standard deviation of the bell curve. However, not all individuals can be helped by the dosing strategy.
5
Q
Why was the original style of dosing initially founded?
A
It was thought to be more cost-effective as manufacturing an individual dose is not. It was also thought that the optimal drug dose can only be determined empirically (through observation).
6
Q
What are the different factors that influence an individual’s response to a medication?
A
Environment
Diet
Age
Lifestyle
State of health
7
Q
What is pharmacogenetics?
A
Pharmacogenetics is the study or clinical testing of genetic variations that give rise to differing responses to drugs. Individual gene concept.
8
Q
What is pharmacogenomics?
A
Pharmacogenomics is the study of how an individual’s genetic inheritance affects the whole body response to drugs. Whole genome concept.
9
Q
What is the promise of pharmacogenetics/ genomics?
A
Will allow for effective drugs to be tailor made for a person’s genetic makeup. It will allow for maximum efficacy and minimum toxicity. It will also prevent adverse effects caused by ineffective and toxic drugs for that person.
10
Q
How has molecular medicine impacted drug administration?
A
Molecular medicine has allowed us to move from trial and error treatment to targeting a specific pathogenic defect. It has allowed us to design drugs better instead of solely moving chemical groups around. It has also allowed us to predict efficacy and toxicity of drugs in individuals.
11
Q
What was the example given for the start of pharmacogenetics?
A
Succinylcholine was used as a muscle relaxer in schizophrenic patients. It should be metabolized in minutes and patients should wake up. Small population did not wake up and it was found that there was a polymorphism in the enzyme that breaks down the drug. The result was that these patients needed to be on mechanical ventilation for longer.
12
Q
What are microarrays used for?
A
They are used to look at the up-regulation and down-regulation of RNA. For example, how does RNA expression look different in those who respond to a certain drug and those who do not respond to that drug?
13
Q
What is pharmaceutical biotechnology?
A
Biotechnology refers to the application of biological systems, living organisms, or their derivatives in making or modifying products of processes for specific use. It is used to manufacture drugs, pharmacogenomics, gene therapy, and genetic testing.
14
Q
What is a biomarker?
A
A biomarker is an indicator for a disease state. Biomarkers must be actionable and impact patient care decisions to be clinically relevant.
15
Q
What is absorption?
A
Transfer of a drug from the site of admin to systemic circulation (blood).
16
Q
What is distribution?
A
Transfer of a drug from systemic circulation (blood) to the tissues.
17
Q
What is elimination?
A
Removal of drug from the body
18
Q
What are the 3 factors that determine the absorption of a drug?
A
- Route of administration (oral, IV, IM, etc)
- Chemical properties
- formulation
19
Q
What is enteral administration?
A
Oral, sublingual, rectal
20
Q
What is parenteral administration?
A
IV, IM, SubQ
21
Q
What are the advantages of enteral admin?
A
Safe
Economical
Convenient
22
Q
What are the disadvantages of enteral admin?
A
Limited absorption (destroyed by digestive enzymes and low pH in stomach)
Irregularities in absorption due to competition with food
Emesis due to gastric irritation
Metabolized by 1st pass effect
23
Q
What is the first pass effect?
A
Oral drugs exposed to liver first are metabolized before reaching systemic circulation.
24
Q
What are exceptions to first pass effect?
A
Sublingual, rectal, IV, IM, SubQ
25
What are the advantages of parenteral administration?
Better regulated with more predictable absorption (no 1st pass)
More accurately select effective dose.
26
What are the disadvantages of parenteral admin?
Risk of infection
Pain with injection
Difficulties with self-medication
27
What area of absorption has the largest surface area?
Small intestine
(mouth and stomach are small with large intestine being bigger)
28
What are the 9 factors that modify absorption throughout the GIT?
1. Solubilization of drug
2. Formulation factors
3. Concentration of drug at absorption site
4. Blood flow at absorption site
5. Surface area of absorption
6. Gastric emptying
7. Food
8. Intestinal motility
9. Metabolism of drug by GIT
29
What is the definition of drug solubilization?
Drug solubilization is the breaking down of drugs into smaller more absorbable particles.
30
What are formulation factors?
Formulation factors are materials added to a drug during processing that can affect the solubilization of the drug. Includes fillers, disintegrators, binders, and lubricants.
31
How does the concentration of the drug at the site of absorption modify the rates of absorption?
The driving force of absorption across membranes is the concentration gradient. The higher the concentration of the drug, the faster the rate of absorption.
32
How does the flow of blood at absorption sites modify the rates of absorption?
Blood flow at sites of absorption maintain the concentration gradient. As blood continues to flow, there is continually more drug in GIT and less in blood allowing this process to continue until all drug enters systemic circulation.
33
How does the surface area of the GIT modify the rates of absorption?
More surface area= more room for things to be absorbed into blood
34
What is the primary site for drug absorption?
Small intestine
35
How does gastric emptying modify drug absorption?
Anything that delays gastric emptying (fatty foods) will decrease drug absorption.
Anything that accelerates gastric emptying will increase drug absorption. This is applicable for all drugs.
36
How does intestinal motility modify absorption of drugs?
If a drug is not completely absorbed before entering small intestine, increasing intestine motility will slow down rates of absorption. Decreasing intestinal motility will increase the rates of absorption.
37
How do metabolic enzymes within the GIT modify drug absorption?
Proteases in GIT break down peptides and microbes in GIT can metabolize certain drugs. Microbes can activate or deactivate drugs
38
What properties of drugs allow them to be permeable to the epithilum?
Small (O2, CO2, H2O)
Hydrophobic/ lipophilic (polarity)
39
What properties of drugs inhibit them from being permeable to the epithilum?
Large and charged (glucose, metallic ions).
40
In a very general sense, how do hydrophilic molecules pass into the cell?
Paracellular diffusion
41
In a very general sense, how to lipophilic molecules pass into the cell?
Transcellular diffusion
42
What are the 4 types of drug transport?
1. Passive diffusion (electrolytes and non-electrolytes
2. Filtration
3. Carrier-mediated transport (active and facilitated)
4. Recepter-mediated endocytosis
43
What is the most common form of movement for drugs?
Passive diffusion
44
What is Kp?
Kp is the lipid-water partition coefficient.
Kp= Conc. of drug in lipid phase/ Conc. of drug in aqueous phase
45
What is the driving force of passive diffusion?
Concentration gradient
46
What are the characteristics of passive diffusion?
Low molecular weighted drugs.
Hydrophilic and lipophilic both.
Driving force is the concentration gradient.
47
A low Kp indicates...
More soluble in water. Molecule is more hydrophilic.
(Katie is LOW on water)
48
A high Kp indicates...
More soluble in lipid. Molecule is more lipophilic
(Katie is HIGH on fatty foods)
49
What is the weak acid equation?
HA --------> H+ + A-
The unionized form (HA, the acid) is the favorable form for absorption. Being uncharged is like being lipophilic.
50
Why is passive diffusion of electrolytes more complicated?
Electrolytes ionize within solutions. They become either weak acids or weak bases.
51
Does a higher Kp allow for faster rates of absorption?
Yes. A higher Kp indicates a more fat-soluble (lipophilic) drug molecule therefore it can cross membranes at a faster rate to enter systemic circulation.
52
What is the weak base equation?
BH+ ------> B + H+
The unionized form (B, the base) is the favorable form for absorption. Being uncharged is like being lipophilic.
53
What is pKa?
pKa is the pH at which half of the molecules are in the ionized/ charged form (water soluble) and half the molecules are in the unionized/ uncharged (Fat soluble) form.
54
What is the henderson-hasselbalch equation?
55
In general, the uncharged/ unionized form of weak acids (HA) and weak bases (B) are ...
Lipophilic
56
In general, the charged/ ionized form of weak acids (A-) and weak bases (BH+) are...
hydrophilic
57
When the pH of the solution is LESS than the pKa of the drug, what form of the weak acid dominates?
unionized/ uncharged weak acid
(HA)
(phu less than pkkaaa, i know your acid is uncharged)
58
When the pH of the solution is LESS than the pKa of the drug, what form of the weak base dominates?
ionized/charged weak base (BH+)
59
When the pH of the solution is GREATER than the pKa of the drug, what form of the weak acid dominates?
ionized/charged weak acid (A-)
60
When the pH of the solution is GREATER than the pKa of the drug, what form of the weak base dominates?
unionized/uncharged weak base (B)
61
What is the driving force of filtration?
Pressure gradient and size of molecule relative to pore (small passes while large is held back)
62
What is filtration in terms of drug transport?
Filtration is the transfer of drugs across a membrane through pores or through spaces between a cell. (Capillary endothelial membranes and renal glomerulus)
63
Lipid soluble molecules typically undergo ___________ for drug transport.
Passive diffusion
64
Water soluble molecules typically undergo ___________ for drug transport.
Filtration
65
What are the 6 characteristics of carrier-mediated ACTIVE transport?
1. Transports important large molecules (sugars, AA, etc)
2. Carrier or receptor-mediated
3. Selective for certain drugs
4. ATP!!!
5. One-way process
6. Inhibition is possible!!
66
What are the 5 characteristics of carrier-mediated FACILITATED diffusion?
1. Carrier or receptor-mediated
2. Selective for certain drugs
3. Saturation is possible
4. NO ATP!!!
5. Two-way process (reversible)
67
What are the differences between facilitated diffusion and active transport?
Active transport requires ATP, is a 1-way process and can be inhibited. Passive diffusion does not require ATP, is bi-directional, and can be saturated.
68
What is receptor-mediated endocytosis?
This is when drugs (hormones, GFs, antibodies, etc) bind receptors on the cell surface in coated pits and then the ligand and receptor are internalized and form endosomes.
69
What is bioavailability?
Bioavailability is the fraction of the administered drug that actually reaches systemic circulation.
Amount of drug that is not metabolized by 1st pass metabolism.
(100mg of drug given orally and 60 reaches systemic circulation. Oral bioavailability is 60%)
70
How can bioavailability be calculated?
(AUC oral/ AUC IV) x100
71
What is bioequivalence?
A measurement of comparison between drugs. Bioequivalence is a measure between two drugs in the areas of max conc. of drug and extent of drug absorption.
72
How is the concentration of a drug calculated?
Concentration= Mass (mg)/ Volume of solution
Volume meaning drug in solution, in blood, or in plasma
73
What are the 4 factors that effect drug distribution?
1. Blood flow
2. Capillary permeability
3. Transfer rate from interstitial fluid into tissues
4. Binding of plasma proteins
74
What areas of the body have the highest perfusion rate?
Perfusion rate is the ratio of blood flow to tissue mass. The highest perfusion rates are in the heart, kidney, liver, lungs, and brain.
75
How does regional blood flow affect drug distribution?
The greater the blood flow to a certain tissue, the more rapid distribution of drug from plasma into interstitial fluid.
76
A drug will appear in the interstitial fluid of the highest perfusion tissues (heart, brain, kidney, liver, etc) _________ than it appears in the lowest perfused tissues (skin, muscle).
Faster
77
Through what process do drugs pass through capillaries?
Filtration
(remember: in filtration, hydrophobic molecules undergo passive transcellular diffusion while hydrophilic drugs needs to use the fenestra for paracellular diffusion)
78
How does capillary permeability affect drug distribution?
Large capillary fenestra allow for a greater filtration potential like in the liver. Small capillary fenestra means a lower filtration potential like in the brain.
79
Where is the interstitial fluid?
Interstitial fluid is surrounding the cells and blood vessels.
80
How is drug distribution affected by plasma proteins?
Plasma proteins bind and hold onto the drug therefore keeping in is systemic circulation longer.
81
When drugs are bound to plasma proteins, they are in there _________ state.
Inactive (no receptor reached, not distributed, not metabolized, not excreted)
82
What are the 3 main types of plasma proteins?
1. Albumin
2. Lipoproteins
3. Alpha1-acid glycoproteins
83
What type of drugs does albumin typically bind to?
Weak acids and hydrophobic drugs
84
What types of drugs do lipoproteins typically bind to?
Hydrophobic drugs.
85
What type of plasma lipoprotein has the strongest binding ability?
VLDL>LDL>HDL
86
How is a patient with good HDL levels affected in terms of drug distribution?
A patient with good HDL levels has less drug binding with HDL allowing drugs to be more efficacious and leave systemic circulation faster.
87
What type of drug do alpha1-acid glycoproteins bind to?
Basic drugs.
88
________ plasma proteins = ________ free drug available
MORE
LESS
89
The placenta is another barrier present in the body like the BBB. What characteristics of the placenta make it much less effective as a barrier?
High in fat content and highly perfused. Molecules less than 600 MW cross barrier easily.
90
What is the apparent volume of distribution?
The apparent volume of distribution is the theoretical volume of fluid into which the total drug administered would have to be diluted to produce the concentration in the plasma.
In simple terms, it is how readily or not the drug will remain in systemic circulation or redistribute to other tissues.
91
What is the volume of distribution equation?
Vd= Dose/ Plasma concentration at time zero
92
What percentage of total body water (interstitial, intracellular, plasma) does plasma make up?
around 4%
93
What does a low volume of distribution mean?
LOW Vd = drug likely to stay in systemic circulation or bound to plasma proteins
94
What is the main purpose of metabolism?
The main goal of metabolism is to increase the hydrophilicity so that it can be secreted in the urine.
95
Metabolism can increase, decrease, or not change the overall __________ and ___________ of a drug.
Toxicity and activity
96
What are the 3 types of drugs metabolism?
Phase I/II metabolism
Phase III metabolism
97
What are the main organs that metabolize drugs?
Liver, kidney, and intestines
98
Basic drugs have a ________ volume of distribution.
High. Basic drugs will go to the tissues
99
Acidic drugs have a _________ volume of distribution.
Low. Acidic drugs will stay in the blood.
100
Metabolism is based on the basic characteristics of what?
(this is the stupid one that compares biotransformation to metabolism)
1. Structural change
2. Emphasis in the outcome
3. Focused on applied science
101
In phase I and II metabolism, what is happening to the drug?
Structural change through the addition of chemical groups.
102
Inside the organelles, where is phase I and II metabolism occuring?
In the microsome (ER) and cytosol. Not in the plasma membrane
103
Inside the organelles, where is phase III metabolism occuring?
Abundantly occurs in the plasma membrane but can occur in the microsome (ER).
104
Are there any hydrophilicity changes to the drug in phase III metabolism?
No, this all occurs during phase I and II.
105
Which phase of metabolism increases hydrophilicity the most?
Phase II increases hydrophilicity the most. The exceptions occur in methylation and acetylation.
(methylation and acetylation are decreasing polarity meaning they are becoming more lipophilic)
106
Which phase of metabolism involves the crossing of cell membranes?
Phase III
107
Which phase of metabolism involves hydrolysis, reduction, and oxidation?
Phase I
108
What are the enzymes involved in phase I hydrolysis?
Carboxylesterases
Cholinesterases
Epoxide Hydrolases
Peptidases
109
What is the function of carboxylesterases in phase I metabolism?
Carboxylesterases hydrolyze esters, thioesters, and amides.
CES1- cleaves unbound compounds
CES2- cleaves bound compounds
110
What is the function of cholinesterases in phase I metabolism?
Colinesterases hydrolyze esters.
111
What is the function of epoxide hydrolases in phase I metabolism?
Epoxide hydrolases hydrolyze epoxides.
112
What is the function of peptidases in phase I metabolism?
Peptidases hydrolyze amides.
113
In phase I metabolism, reduction is a relatively minor pathway. What are the two types changes in reduction that turn 1 molecules into 2?
Addition of an Azo group (N=N) and disulfide groups (S-S). Overall reduction adds an H atom.
114
In phase I metabolism, oxidation is the most common type of change. What percentage of molecules undergo oxidation as their form of phase I metabolism?
90%
115
Does oxidation require cofactors?
Yes, oxidation of molecules in phase I metabolism requires cofactors. They include NAD, FAD, and molybdenum.
116
What are the 7 enzymes that participate in oxidation reactions in phase I metabolism?
1. Alcohol dehydrogenase
2. Aldehyde dehydrogenase
3. Aldehyde oxidase
4. Xanthine oxidase
5. Monoamine oxidase
6. CYPs
7. FMOs
(Oxidation includes the +oxygen or the -hydrogen)
117
What are the two most important enzymes in phase I oxidation?
CYPs and FMOs
118
Do CYPs or FMOs have more functional genes?
CYPs (57 functional) have more overall and functional genes compared to FMOs (5 functional)
119
What is the prosthetic group (molecules needed in order for the enzyme to function) in CYPs?
Heme-Fe
120
What is the prosthetic group in FMOs?
FAD
121
What is the affinity and capacity of CYPs?
CYPs have high affinity but low capacity.
122
What is the affinity and capacity of FMOs?
FMOs have low affinity but higher capacity.
123
What is 1-aminobenzotriazole?
This is a substance used in lab work to knock out CYPs in order to see if CYPs or FMOs metabolize a drug.
124
What are the 2 FMO types involved in disease development?
FMO3 and FMO5
125
Which FMO is the most broad?
FMO1
126
Why are CYPs called CYP450?
CYPs are called CYP450 because when it is attached to CO, spectroscopy absorbs it at a wavelength of 450.
127
What are the 4 characteristics of CYP450s?
1. Absorbed at 450 wavelength
2. Catalytic cycle
3. Slow (catalytic cycles are slow)
4. Reductase involved
128
What percentage of drugs are metabolized by CYP3?
50%
129
What are phase II reactions?
Phase II reactions are conjugation reactions. Included addition of acetyl groups, methyl groups, glucuronic groups, glutathione groups, and sulfo groups.
130
What is the most abundant enzyme in phase II metabolism?
1. UGTs (UDP glucuronosyl-transferases)
2. GSTs (glutathione S-transferases) and SULTs (sulfotransferases)
131
What is the purpose of methylation in phase II metabolism?
Goal of methylation is to decrease the polarity of the drug molecule.
132
What is the donor molecule for methylation in phase II metabolism?
S-adenosylmethionine (SAM)
133
What are the major enzymes that function in methylation for phase II metabolism?
N- O- S-
methyltransferases
134
What is the purpose of acetylation in phase II metabolism?
The goal of acetylation is to decrease the polarity of the drug molecule and increase transporter affinity.
135
What are the majors enzymes that act in acetylation in phase II metabolism?
NAT1 and NAT2
136
What are the two drug examples that undergo acetylation in phase II metabolism?
Sulfamethoxazole and Isoniazid
137
What is the donor molecule for acetylation in phase II metabolism?
Coenzyme A
138
What is the purpose of glutathione conjugation in phase II metabolism?
The purpose of glutathione conjugation is to increase polarity and transporter affinity. Drug molecules that undergo glutathione conjugation are very hydrophilic to start.
139
What is the donor molecule for glutathione conjugation in phase II metabolism?
Glutathione
140
What is the major enzyme that participates in glutathione conjugation in phase II metabolism?
GST
141
What are the two examples of drugs that undergo glutathione conjugation?
Acetaminophen and Cisplatin
142
What is the major pathway in phase II metabolism?
Glutathione conjugation
143
What is the purpose of sulfation in phase II metabolism?
The purpose of sulfation is to increase polarity greatly. Drug molecules that undergo sulfation are very hydrophilic to start.
144
What is the donor molecule for sulfation in phase II metabolism?
PAPs
145
What is the major enzyme that participates in sulfation in phase II metabolism?
Sulfotransferases (these have a higher affinity than UGTs)
146
What are the two drug examples that undergo sulfation in phase II metabolism?
Acetaminophen and Estrone
147
What is the purpose of glucuronidation in phase II metabolism?
The purpose of glucuronidation is to increased the polarity of the drug molecule and increase capacity.
148
What is the donor molecule in glucuronidation in phase II metabolism?
UDPGA
149
What is the enzyme that participates in glucuronidation in phase II metabolism?
UDP glucuronosyl-transferases (UGTs)
150
What are the two examples of drugs that undergo glucuronidation in phase II metabolism?
Chloramphenicol and Valproate
151
Phase II reactions in general favor excretion of the drug by _____________ affinities towards transports which can be done by increasing, decreasing, or not changing the lipophilicity of the drug molecule.
INCREASING
152
What are the two example drugs that undergo methylation in phase II metabolism?
Azathioprine and Apigenin
153
What is phase III metabolism all about?
Phase III metabolism is about membrane-transport. It requires energy and moves against concentration gradients.
154
What are the two major types of phase III drug transport families?
ATP-Binding Cassette (ABC) transporters and Solute Carrier (SLC) transporters (SLCs include the OATs)
155
What is the function of ATP-Binding Cassette (ABC) transporters?
Efflux. They transports drugs out of the cell.
156
What is the function of Solute Carrier (SLC) transporters? What is unique?
Typically OATs uptake drugs into the cell. However, OAT4 does uptake and efflux.
157
What type of transporter transports substances out of a cell in regards to phase III metabolism?
Could be either ATP-binding cassette transporter or solute carrier transporter (OAT4 does efflux and influx).
158
How does enterohepatic circulation effect phase III metabolism?
Enterohepatic circulation occurs when the lipophilic and uncharged drugs are metabolized by the liver but is secreted into the bile. The bile enters to small intestine and is reabsorbed. This process continues in a loop. This process prolongs drug action and exposure.
159
Where is the dominant location of phase III metabolism within the cell?
Plasma membrane
160
What are the four factors that affect drug metabolism?
1. Physiological conditions
2. Disease states
3. Environmental exposure
4. Genes
161
What are the 4 physiological conditions that effect drug metabolism?
1. Circadian rhythm- CYP upregulated in morning and downregulated at night. 60% of liver enzymes undergo circadian gene regulation.
2. Pregnancy
3. Sex- sex differences like BW, surface area, muscle, fat, gastric acid, and hormones
4. Age- older people have decreased drug metabolism
162
What are the 3 classes of ontogenic expression patterns?
Class 1- highest level during neonatal and fetal stage followed by gradual decrease
Class 2- expressed independently of age
Class 3- Low levels followed by a surge at birth. Represents the majority of genes related to metabolism
163
How do disease states effect metabolism?
Disease states will decrease the enzyme ability to metabolize drugs.
164
What is the definition of a polymorphism?
Polymorphism is a genetic variation that occurs at a frequency greater than 1% (mutation is less than 1%).
165
Enterohepatic circulation prolongs drug exposure during which phases?
Phase I, II, and III
165
What are the 4 types of polymorphisms?
1. SNPs
2. Deletion
3. Insertion
4. Multiplicity of genes
166
An alteration in a gene sequence occurs at a frequency of 1.3%. What would this be classified as?
Polymoprhism
167
As star system that categorizes SNP polymorphism ends in a 2 or 3. What does this mean?
This means that the gene is not functional.
168
What are the 4 consequences of environmental exposure to drug metabolism?
1. inhibition
2. stimulation
3. downregulation
4. induction
169
What are the 3 types of inhibition that can be seen due to environmental exposure?
1. Competitive
2. Non-competitive
3. Mechanism-based
170
What are 3 main characteristics of competitive inhibition?
1. Inhibitor is a substrate
2. Inhibition is REVERSIBLE
3. Inhibition can be overcome by increase concentration of substrate
171
What is an example of competitive inhibition?
CYP2C19
Substrate is omeprazole. Inhibitor is diazepam.
172
What are the 3 main characteristics of non-competitive inhibition?
1. Inhibitor is NOT a substrate
2. Inhibition is REVERSIBLE
3. Inhibition cannot be overcome by enough substrate
173
What is an example of non-competitive inhibition?
CYP3A4
Substrate is Quinidine
Inhibitors are cholesterol and ketoconazole
174
What are the 3 main characteristics of mechanism-based inhibition?
1. Inhibitor is NOT a substrate
2. Inhibition is NOT reversible
3. Inhibition can NOT be overcome by enough substrate
175
What is an example of mechanism-based inhibition?
CES2
Substrate is Irinotecan
Inhibitors are Orlistat and Sofosbuvir
176
Phospholipids _______ P450 activity.
Activate
177
________ induce CYP3A4 structural changes.
Flavonoids
178
Parathyroid hormone _________ CYP3A4 and ABCG2.
downregulates
178
Cytokines _________ CES1, CES2, and CYP3A4.
downregulate
179
What nuclear receptor is the master regulator of gene expression?
PXR. This is due to its large ligand binding area that can handle large and diverse compounds.
180
What is induction?
This is the process of gene activation by an inducer molecule resulting in the transcription of genes.
181
What is the prototypical activator for PXR?
Rifampicin
182
What would happen if you had a PXR inducer and a PXR ligand together?
It would lead to superinduction.
183
Which of the following is not true?
A. CYP3A4/5 contribute 50% to Phase 1 biotransformation
B. Renal dysfunction likely has great impact on drug elimination
C. Inflammation causes no changes to drug metabolism
D. Overexpression of P-glycoprotein causes chemoresistance
C. Inflammation decreased the ability of phase I, II, and III metabolism.
184
Which of the following does not increase hydrophilicity?
A. Glutathione conjugation of cisplatin
B. Methylation of azathioprine
C. Sulfation of estrone
D. Glucuronidation of chloramphenicol
B. Methylation of drugs during phase II metabolism increases the polarity of a drug making it more lipophilic, not hydrophilic.
185
Which of the following is not true?
A. Sulfation requires PAPs
B. Flavin adenine dinucleotide is required for hydrolysis
C. Coenzyme A is involved in drug acetylation
D. S-Adenosylmethionine is a cofactor for drug methylation
B. FAD is required for FMOs in phase I metabolism, not in hydrolysis.
186
Which of the following does not causes changes in therapeutic activity?
A. Hydrolysis of clopidogrel
B. Conversion of iproniazid to isoniazid
C. Reduction of prontosil
D. Conversion of amitriptyline to nortriptyline
D. Conversion of amitriptyline to nortriptyline causes no changes in activity.
187
Which of the following is not true?
A. CYP-based catalysis does not need reductase
B. Mechanism-based inhibition permanently inactivates an enzyme
C. Acetylation increases lipophilicity
D. Two substrates for the same enzyme function as competitive inhibitors towards one another.
A. CYP-based catalysis does require reductase.
188
A weak acid drug with a pka of 5 is taken orally and enters the stomach. Is this drug absorbed through the stomach or does it enter into the GIT?
Because the pH of the stomach is around 2, the pH here is less than pKa. That means the uncharge form of the weak acid will dominate (HA). Because uncharged is like lipophilicity, the weak acid can diffuse across the stomach and enter systemic circulation bypassing the GIT.
189
Aspirin, an FDA approved drug has carboxyl (COOH) functional group and a pKa of 3.5. Predict where the drug is absorbed.
A. Mouth
B. Stomach and Duodenum
C. Ileum and large intestine
The stomach and duodenum
(Aspirin is a weak acid)
190
What are the main sites for drug excretion?
1. Kidney as urine
2. Liver as bile
3. Skin as sweat and saliva
4. Lung as air
5. Milk in lactating female
191
What is glomerular filtration that occurs in renal excretion of drugs?
This is when drugs are filtered from the blood (afferent arteriole), into the urine, located inside the glomerulus.
192
What is the driving force behind glomerular filtration?
Hydrostatic pressure
193
What types of drugs cannot undergo glomerular filtration?
Large (>50K), charged, and protein bound drugs have a hard time being filtered.
194
What is active secretion that occurs in renal excretion of drugs?
This is when drugs are secreted from the blood into the urine in the proximal tubule. Active transport system that requires energy, can be saturated, unidirectional, competitive, and is fairly non-specific.
195
What type of drugs can undergo glomerular filtration?
Small (<30-50K daltons), cations (membrane is - charged and opposites attract), and free drugs.
196
Where is the main place that active secretion takes place?
Proximal tubule
197
What type of transport is active secretion very similar to?
Active secretion in renal excretion is very similar to active transport as it can be saturated, unidirectional, requires energy, and is competitive.
198
What is passive reabsorption in renal excretion and where does it take place?
Passive reabsorption is reabsorption of unionized and lipophilic drugs into the blood. Passive reabsorption takes place along renal tubules.
Can be active or passive
199
What are the two types of molecules that undergo passive reabsorption?
Unionized and lipophilic drugs
200
___________ of urine causes the reabsorption of ______________ and the secretion of ________ drugs.
Acidification
weak acids
weak bases
(This is because in acidic conditions, weak acids are unionized and can be reabsorbed.
201
If the urine is ________, then acidic drugs will be secreted while basic drugs will be reabsorbed.
Basic
(This is because at a basic pH, acids are ionized (charged) and cannot reabsorbed therefore they are secreted)
202
What are the biological factors that effect renal excretion of drugs?
Sex- 10% lower in females
Young Age- newborn at 30-40% less
Old Age- GFR reduced resulting in slow excretion and longer half-lives
203
Which statements are true about liver secretion?
A. Enterohepatic recycling prolongs drugs action
B. Water soluble drugs are more likely to undergo enterohepatic recycling
C. Liver has large fenestrae which allow for drug filtration
C. Due to the liver's bile capillaries, there are no active secretion processes in the liver
A and C.
Lipid soluble drugs are more likely to undergo enterohepatic recycling. Drugs are actively transported from hepatocytes into the capillaries by 4 different systems specific to acids, bases, neutral compounds, and bile acids.
204
What is clearance?
Clearance is the volume of blood in a defined region of the body that is cleared of a drug in a unit of time.
CL= Ke(elimination rate constant) x Vd
205
How does volume of distribution affect clearance?
Based on Clearance= Ke x Vd
The larger the Vd, the larger the rate of clearance is.
A drug with a small Vd has a low rate of clearance.
206
What is half-life?
Half-life is the time required to reduce the plasma concentration of a drug by 50%.
207
What are the two components that affect half-life?
Volume of distribution and clearance
(Increased Vd leads to increased half-life)
208
What is the half-life equation?
t1/2= 0.693/ke
OR
t1/2= 0.693 (Vd/CL)
209
What is first-order elimination?
First order elimination is elimination proportional to the concentration of the drug. It has exponential decrease and the half-life is constant regardless of the amount of drug in the body.
210
What is zero-order elimination?
This is elimination that constant regardless of concentration and follows a linear decrease. Drugs here do not have a constant half life. Includes things like ethanol, aspirin, and phenytoin.
211
Why is half-life relevant?
Half-life of a drug determines the frequency a drug needs to be dosed at.
212
What are the 4 ways in which drugs interact with their drug target?
1. Electrostatic interactions- includes hydrogen bonds and van der waals
2. Hydrophobic interactions
3. Covalent bonds
4. Stereospecific interactions
(S Carvedilol binds to alpha and beta adrenergic receptors while R Carvedilol binds to alpha adrenergic receptors)
213
Want the following bonds from strongest to weakest...
Covalent, van der waals, hydrogen, and ionic
1. Covalent- two molecules sharing a bond. Irreversible in relation to drugs (ex: Phenoxybenzamine (alpha-antagonist) binding to alpha-adrenergic
receptors, nerve gas)
2. Ionic
3. Hydrogen
4. Van der waals
214
What are key points of the drug target theory?
1. The drug induces a unique change in the conformation of the target
2. Drug is not altered by the interaction with the target
215
What are the 4 drug target subtypes?
1. Enzymes
2. Membrane receptors
3. Intracellular receptors
4. Ion channels
215
Regulatory proteins in the cell membrane are _______ proteins and has a binding pocket. What are the two conformations?
Receptor
Resting conformation and active conformation
215
What are small molecule kinase inhibitors?
These are a new class of drugs that suppress cellular signalling by either competing with ATP binding (type I inhibitor) or trap the cell in its inactive state (type II inhibitor).
215
What are the 3 main receptor proteins?
1. Tyrosine Kinase receptor
2. G-protein coupled receptor
3. Steroid hormone receptor
216
Describe the action of the tyrosine kinase receptor.
1. Two seperate tyrosine kinase receptors present in cell membrane when ligand binds
2. receptors dimerize
3. tyrosine ends phosphorylate each other (autophosphorylation)
4. Molecules in the cell go to the tyrosines to become phosphorylated
5. Molecules enter a transduction pathway and it leads to a cellular response
217
Describe the action of the G-protein coupled receptor.
1. Resting receptor, GDP and GDP
binding protein (with αβy subunits),
and effector.
2. An agonist binds to the receptor
3. The αβy subunit dissociates with
receptor and GDP is replaced with
GTP (this activates the receptor).
4. α-GTP dissociates and attaches the
effector
5. α hydrolyzes GTP to GDP
6. The receptor is inactivated.
7. A second messenger is generated (typically cAMP)
218
Describe the action of the steroid hormone receptor.
The steroid hormone receptor is located within the cell as lipophilic molecules to it.
In a very general sense, lipophilic molecules binds to these receptors. The bound complex enters the DNA and acts as a transcription factor to alter transcription.
219
What are the two types of ion channels?
Voltage activated Na+ channels and Ligand-gated Na+ channels
220
Which of the following drug receptors activate cell signalling (cell signalling is the entire process of the receptor binding, transduction of signal, and finally a response in the nucleus)?
A. Ion channels causing changes in ionic conductance
B. Intracellular targets activating transcription/translation
C. Transmembrane receptor linked with a G protein
D. Transmembrane receptor linked with JAK-STAT enzyme
C and D
GPCR have eventually have a-GTP that dissociates and binds to effector which generates second messengers. JAK-STAT is similar to tyrosine kinase receptors but it activates STAT.
221
Describe an example of ligand-agted Na+ channels.
Acetylcholine (ACh) binds to ion channel and allows for the passage of sodium (Na+) through to facilitate the contraction of muscle.
222
Which ligand allows for the passage of Na+ through ion channels? Is that action excitatory or inhibitory?
Acetylcholine (ACh) and it is excitatory
223
What is the second messenger in G protein signal transduction?
Typically cAMP (also can be IP3, DAG, and Ca2+)
224
Ion channels cause a change in ________________.
Membrane potential
225
What is the result of a steroid binding to an intracellular receptor?
A. A change in membrane potential
B. Dimerization and cross phosphorylation
C. Changes in gene transcription
D. Vasodilation
C
Steroid hormones bind to steroid hormones receptors and go into nucleus to alter gene transcription. A change in membrane potential is caused by ion channels, Dimerization and cross phosphorylation occurs in tyrosine kinase receptors. Vasodilation occurs with nitric oxide and cGMP
226
For the tyrosine kinase pathway (insulin or EGF), what does the binding of the ligand initiate?
A. Dimerization or cross phosphorylation
B. The generation of a second messenger
C. A change in membrane potential
D. Changes in gene transcription
A
It can induce second messengers but the question asked what did the ligand initiate.
227
What is efficacy?
Efficacy is the ability of an agonist to produce its biological effects
228
What is a reverse agonist?
Reverse agonist produce the opposite effect compared to what an agonist would do
229
What is physiological antagonism?
Physiological antagonism is when the drug antagonizes one biological mechanism but activating an opposing compensatory effect.
230
What is chemical antagonism?
Chemical antagonism is when a drug reduces an active agonist by forming a chemical complex with it.
231
What are pharmacokinetic antagonists?
Pharmacokinetic antagonists are drugs that accelerate the metabolism or elimination of another drug.
232
What is potency?
Potency is a measure of the drug physiological activity expressed in terms of the dose required to produce a pharmacological effect for a given intensity.
233
Describe the potency of the following drugs in the graph.
Drugs closer to the Y axis (to the left) are more potent.
234
Describe the efficacy of the following drugs in the graph.
The taller the line, the more efficacious a drug is.
235
What is specificity?
Specificity of a drug has only one effect on all biological systems. If the drug exerts multiple biological effects it would be non-specific.
The preference of an enzyme for one specific substrate.
"I specify 1 effect"
236
What is selectivity?
Selectivity of a drug means that at low concentrations, the drug acts on only one receptor site. At high concentrations, it may engage multiple receptors and is non-selective.
The preferance of one substrate over another.
"I select only 1 receptor"
237
What is the therapeutic window?
The therapeutic window is the concentration range over which the drug produces it therapeutic effect. It is basically the range of satisfactory efficacy with acceptable toxicity.
Theraputic window is the difference between TD50 and ED50. (can use number other than 50 however)
238
What is the therapeutic index?
The therapeutic index is ratio that expresses the relationship between TD50 and the ED50
239
What happens to potency and efficacy if a competitive antagonist is added with an agonist?
The curve will shift to the right because more of the agonist will need to be added to overcome to antagonist. There are no changes to efficacy as the agonist can still exert its full effect if enough is added.
240
What happens to potency and efficacy if a noncompetitive antagonist is added with agonist?
When a non-competitive antagonist is added with an agonist, the non-competitive antagonist takes away those receptors. No matter how much agonist is added, it cannot overcome the non-competitive antagonist. This reduces the efficacy of the drug but does not effect the potency as no additions of the agonist can produce an effect.
241
T or F: All phase II reactions require donors (cofactors).
True
242
T or F: Phase I and II but not III biotransformation reactions cause structural changes to the molecule.
True
243
T or F: The pregnane X receptor (PXR) is the master regulator characterized by ligand diversity, species difference, and individual variation.
True
244
Which of the following must be submitted prior to the beginning of clinical trials of a potential therapeutic agent?
IND
245
cAMP is generated in the signal transduction pathway initiated by which receptor type?
GPCR
246
Which of the following exerts it effect by increasing the concentration of cGMP following the activation of soluble guanylate cyclase?
Nitric oxide
247
T or F: By definition, a partial agonist is less potent than a full agonist.
Flase. A partial agonist is less efficacious than a full agonist.
248
Diphenhydramine, has an anime functional group and a pka of 8.8. Predict which plasma protein it will bind to.
Albumin. Diphenhydramine is an exception to the rule that mainly acidic and hydrophobic drugs bind to albumin as this drug is a weak base in solution.
249
Dosing is important for giving medications. However, the drug ____________ is what really matters for the drug effect.
Concentration
250
What are the two factors that dose is related to and impacts and individual's dosing?
Body mass and body surface area
251
When is body surface area used for drug administration?
Body surface area is used in the pediatric population.
252
Why can obesity be a problem when dosing drugs?
Obesity causes lipophilic drugs to be dragged into the adipose tissue and substantial increases of drug dosing need to be done. However, adverse effects include an overdose due to lipophilic drugs leaking back into systemic circulation.
253
What is a generic drug?
A generic drug is comparable to a brand listed drug in dosage form, strength, route of admin., safety, efficacy, and intended use. It must contain the same active ingredient as the brand name.
254
What are the FDA requirements for a generic drug?
The generic drug must have identical PK and PD and have an acceptable bioequivalence to the brand name drug.
255
What is true about the regulation of dietary supplements? Choose all that apply.
A.Require proof of safety and efficacy
B. Not allowed to market as treatment for cure of a disease
C. Considered OTC drug
D. FDA is responsible for safety and efficacy regulation
B and D
FDA is responsible under the DSHEA act
256
What are the characteristics of simple short peptides as drugs?
- can be completely humanized
- large amount of recombinant proteins
-efficient and inexpensive
-generics can be produced
257
What are the characteristics of proteins as drugs?
- must be injected
-stability and solubility affect drug action
-possible immune response
-half-life can be affected by proteases
258
Which statements are true about biological drugs?
A. Produced by chemical synthesis
B. High molecular weight
C. Complex, heterogenous structure
D. Process independent
C. Highly stable
D. Non-immunogenic
B and C
Chemical drugs and generics are produced by chemical synthesis, are process independent, and are non-immunogenic. Biological drugs are not very stable.
259
What are the differences between chemical drug/generics and biologics/biosimilars?
Chemical drugs have a low molecular weight, simple structure, are chemically produced, have standardized manufacturing process, the same molecule can be obtained, stable, non-immunogenic, and need to be bioequivalent.
Biologics/biosimilars havea. high molecular weight, complex structure, made by living cells, have a specialized manufacturing process, variety among batches, sensitive to breakdown, and are immunogenic.
260
T or F: Biologics and biosimilars have no clinically meaningful differences in terms of safety and efficacy with the reference product.
True. Biosimilars are the "generic" versions of biologics. They have the potential to exhibit different therapeutic effects but there are no significant difference in safety and efficacy.
261
Explain isoniazid toxicity in the terms of pharmacogenetics.
Isoniazid was given for tuberculosis. Those with high drug level had interactions with vitamin B6 causing peripheral neuropathy. It was found that these individuals could not degrade drugs via acetylation due to a deficiency in N-acetyltransferase
262
Explain primaquine toxicity in terms of pharmacogenetics.
Primaquine caused hemolysis in African Americans. It was found that they lacked the enzyme glucose-6-phosphate dehydrogenase. This deficiency allowed for protection against malaria.
263
What are the two types of receptors that their excess activity can cause breast cancer?
Estrogen receptors and EGF receptors (HER2)
264
Herceptin (trastuzumab) is only effective in the treatment of breast cancers that express _________.
Her2/neu
265
What is the function of the drug herceptin?
Herceptin binds to her2-neu receptors and blocks it activity.
266
T or F: Herceptin can be used for all breast cancers.
False. Herceptin can only be used in breast cancers that express the Her2/neu receptor. Estrogen based breast cancers must be treated with anti-estrogens.
267
What are the two main benefits of pharmacogenomics?
1. Assessment of disease predisposition
2. Determination of drug responses
268
A lack in which receptor may lead to mycobacterium avium infections?
Interferon-gamma1.
This is a protein that helps the immune system. In those with a deficiency in the interferon-gamma1, the immune system cannot use it to fight off mycobacterium.
269
What affected allele affects a person response to pravastatin?
ApoE allele. This is related to the CETP (cholesteryl ester transferase protein)
270
Asthma has a genetic component. Bronchodilators, are used to treat it. A patient's response to this drug can be linked to the haplotype of which receptor?
Beta-adrenergic receptor
271
What are haplotypes?
Haplotypes are SNPs that are so close together that they are inherited into the next daughter cell.
272
What is theranostics?
Theranostics is the development of diagnostic tests directly linked to therapeutic applications. (ex: radioactive iodine tracers to detect thyroid cancer)
273
What is genostratification?
This is the use of genetic tests to determine patient enrollment in clinical trials.
274
What do drug target mutations effect in terms of pharmacodynamics in pharmacogenetics?
Pharmacodynamic drug transport mutations affect drug actions. These mutations are typically not inactivating.
275
What does the drug metabolism effect in terms of pharmacokinetics in pharmacogenetics?
Pharmacokinetic drug metabolism mutations affect drug activation and disposition. Mutations here at typically inactivating.
276
What does the drug transport effect in terms of pharmacokinetics in pharmacogenetics?
Pharmacokinetic drug transport mutations affect drug distribution. Mutations here are typically not inactivating.
277
Mutations in drug transport effects drug ______________.
distribution
278
What are drug targets and what do they include?
Drug targets are any gene product involved in the pharmacologic action of a drug. Drug targets include direct protein targets, proteins involved in the pharmacologic response, proteins associated with disease risk, and proteins associated with toxicity.
279
What is drug target pharmacogenetics?
Drug target pharmacogenetics is the contribution of genetic variability in drug targets to either variable drug efficacy or drug toxicity.
280
What are the actions of the beta-1 receptor? (bound by NE and EPI)
The beta-1 receptor increases HR, increases contractility, and increases lipolysis.
281
Where are the three locations of the beta-1 receptor?
SA node of the heart (increases HR)
Cardiac muscle (increases contractility)
Adipose Tissue (Increases lipolysis)
282
Which of the following are the actions of the beta-1 receptor?
A. Increase HR
B. Bronchodilation
C. Increased lipolysis
D. Relaxed Uterine walls
E. Increased contractility
A, C, and E
283
What are the main locations of the Beta-2 receptor?
Bronchial smooth muscle (dilates bronchioles)
GI smooth muscle (constricts sphincters and relaxes gut wall)
Uterus (Relax uterine wall)
Bladder (relax bladder)
Liver (increase gluconeogenesis and glycolysis)
Pancreas (increase insulin release)
284
What are the functions of the beta-2 receptor?
Dilates bronchioles, constricts sphincters and relaxes gut wall, relaxes uterine and bladder wall, increase gluconeogenesis and glycolysis, and increase insulin release.
285
Where is the beta-3 receptor located and what is it function?
The beta-3 receptor is located in the adipose tissue and functions to increase lipolysis.
286
Polymorphism in the ____________ receptor alters the response to metoprolol.
Beta adrenergic receptor. Arg389 carriers have a greater hypertensive response to metoprolol.
287
What is the combination of therapy for HIV/AIDS?
Nucleoside analogs (target nucleic acid synthesis)
Protease inhibitors (Target viral assembly)
Reverse transcriptase inhibitors (target reverse transcription)
HAART
288
What is HAART and what drugs does it include?
HAART is the highly active antiretroviral therapy given to those with HIV/AIDS.
It includes 2-3 nucleoside analogs, 1-2 protease inhibitors, or 1 reverse transcriptase inhibitor.
289
What subset of cells are majorly being suppressed in HIV/AIDS?
Chemokines and CD4
290
A deletion in _________ gene provided resistance to HIV.
CCR5
291
What is the most important efflux transporter?
ABCB1 (pgp-1 and MDR)
292
Where is ABCB1 expressed?
Liver, intestines, kidney, pancreas, adrenals, BBB, BTB, and placenta
293
What are the substrates for ABCB1?
Hydrophobic and amphipathic (hydrophilic and hydrophobic) drugs. Endogenous substrates as well like corticosteroids and lipids. Includes anti-cancer agents, cardiac drugs, HIV protease inhibitors, immunosuppressants, antibiotics, antihistamines.
294
Which of the following would be a substrate for ABCB1?
A. Hydrophobic/amphipathic drugs
B. Hydrophilic drugs like ASA
C. Polar drugs
D. Endogenous substrates
A and D
295
The higher the expression of ABCB1 means the __________ the drug resistance.
Higher
296
What is the relationship between digoxin and quinidine in regards to ABCB1?
Digoxin and quinidine compete for ABCB1. Combining the two therapies allows for higher systemic concentrations of Digoxin.
297
What is the relationship between digoxin and rifampin in regards to ABCB1?
Rifampin induces the expression of ABCB1 therefore blood concentration of digoxin are reduced when taken together. This can lead to atrial fibrillation and CHF as digoxin is used to treat those.
298
T or F: An enzyme inducer like rifampin would increase digoxin concentrations.
False. Rifampin would decrease the blood concentrations of digoxin.
299
Polymorphisms in the MDR-1 (just p-glycoprotein of the brain) transporter in the BBB are responsible for ____________ and ______________.
Drug-resistant epilepsy and postural hypotension with nortriptyline use.
300
What is the most common form of transport for substances to get into the brain?
Transcellular
301
What are the 4 types of transport through the BBB and into the brain?
1. Transcellular
2. Transport proteins
3. Receptor-mediated endocytosis
4. Adsorptive endocytosis
302
What is the blood-testis barrier (BTB)?
This is a physical barrier between the blood vessels and the seminiferous tubules of the testis formed by tight junctions between sertoli cells.
303
What are the substrates, inducers, and inhibitors of CYP1A2?
Substrate: Caffeine and Estradiol
Inducer: Smoking
Inhibitor: Fluroquinolones
304
What are the substrates, inducers, and inhibitors of CYP2A6?
Substrate: Nicotine and Coumarin
Inducer: NA
Inhibitor: NA
305
What are the substrates, inducers, and inhibitors of CYP2B6?
Substrate: Methadone
Inducer: Phenobarbital
Inhibitor: Thiotepa
306
What are the substrates, inducers, and inhibitors of CYP2C8?
Substrate: Retinoic acid and chloroquine
Inducer: Rifampicin
Inhibitor: Trimethoprim
307
What are the substrates, inducers, and inhibitors of CYP2C9?
Substrate: Ibuprofen and tamoxifen
Inducer: Rifampicin
Inhibitor: Amiodarone
IT is an RA in room 2C9
308
What are the substrates, inducers, and inhibitors of CYP2D6?
Substrate: Codeine and metoprolol
Inducer: Dexamethasone
Inhibitor: Methadone
308
What are the substrates, inducers, and inhibitors of CYP2E1?
Substrate: Acetaminophen
Inducer: Ethanol
Inhibitor: Disulfiram
309
What is the relationship between debrisoquine and CYP2D6?
Debrisoquine is used to treat high BP. It is metabolized by CYP2D6 to its inactive form and is secreted in the urine. It was one of the first drugs studied looking at CYP2D6 metabolism variations among individuals. Poor CYP2D6 metabolizers experienced prolonged drops in BP.
310
What enzyme is primarily responsible for the metabolism of many antidepressants (nortriptyline)?
CYP2D6
311
What are the two new approaches to drug design?
1. Random high throughput screening- make millions of chemicals and fish out which ones work
2. Deterministic rational drug design- get structure of drug target and via computer program decide which molecule fits best
Or combine the two
312
What are chemical libraries?
This is a large collection of chemical compounds. They are used to test how different compounds interact with biological targets (i.e., proteins or enzymes). Researchers generate a library of chemicals in an attempt to find which one binds with the
highest affinity to the target.
313
The bigger the chemical library, the _________ chances of success in drug discovery.
Higher
314
Low expression activity polymorphism in __________ densensitizes patients to methotrexate.
SLC19A1
315
What is the drug methotrexate designed to mimic?
Folate. Folate is needed for cell division and methotrexate blocks the folate binding site.
316
What are the two ways in which peptide or protein drugs are synthesized?
1. Automated peptide synthesizer
2. Cloning and expression in prokaryotes and eukaryotes
317
What is the process of DNA cloning?
DNA cloning introduces the target DNA into the cloning vector like a plasmid. Not all plasmids take up the DNA so a drug or solution is used to kill only the vector that did not take up the DNA. Only left with the host cell containing the target DNA.
318
What are the 6 expression systems for synthesizing peptides and protein drugs?
E.Coli, Bacillus Subtilis, Yeast, Baculovirus, mammalian cells, and transgenic plant and animals.
319
Which of the expression systems has the most rapid growth, high yield, and the lowest cost?
E. Coli
320
How were protein drug synthesized in the past?
Pig pancreas enzymes. This became too expensive to isolate and the animal sources were limited. In addition, there were reactions to animal product too.
321
What are the 4 functional classification groups for protein therapeutics?
Group 1- Enzymes and regulatory proteins. For endocrine and metabolic disorders. Includes insulin, GH, blood products.
Group II- Targeted proteins. Includes monoclonal antibodies.
Group III- Protein vaccines. Includes Hepatitis B, Lyme disease vaccine.
Group IV- Protein diagnostics. Look for hepatitis C antigen for detection of hepatitis C infection or HIV antigen for HIV infection.
322
Protein vaccines, like the hepatitis B vaccine, belong to which group of protein therapeutics?
Group III
323
What was the first antibody drug generated?
Rituximab for the treatment of B-cell non-Hodgkin lymphoma. This is a chimeric antibody.
324
What are murine antibodies?
These are antibodies that come from mice and rats. It contains no human aspect.
325
Looking at the structure of an antibody, where does the antigen bind?
The antigen binds on the forearms of the antibody.
326
What is a chimeric antibody?
A chimeric antibody is contains 70% human genes.
327
What is a CDR-grafted antibody?
This is a humanized antibody that contains 90% human genes. The FDA will only approve monoclonal antibody drugs if they are at least 90% humanized.
328
What is the source suffix for a human monoclonal antibody?
-u-
329
What is the source suffix for a mouse monoclonal antibody?
-o-
330
What is the source suffix for a chimeric monoclonal antibody?
-xi-
331
What is the source suffix for a humanized monoclonal antibody?
-zu-
332
What percentage of human genes are in a humanized monoclonal antibody?
90%
333
What are the benefits of using new-anti-cancer drugs like small molecule kinase inhibitors and antibodies over the conventional approach?
A. They are cost effective
B. They are more specific
C. They can be used for any cancer
B
334
What is the chemical basis behind the development of methotrexate?
A. Binds folate to inhibit its action
B. Prevents folate from binding through covalent bonding
C. Mimics folate and binds to active site on dihydrofolate reductase
D. Activates dihydrofolate reductase to block folate production
C
335
What is the pathophysiology behind rheumatoid arthritis?
This is an autoimmune disease involving cytokines like TNFa and Interleukin 1. TNFa induces capillary leakage and cartilage degradation. IL-1 contributes to the manifestation of RA as well.
336
What is the goal behind the treatment of rheumatoid arthritis?
To bind and stop TNFa and IL-1 from binding to their receptors.
337
What is the source suffix for a primate monoclonal antibody?
-i-
338
What is the functions of Infliximab (Remicade) and Adalimumab (Humira)?
These drugs function by binding to TNFa in the bloodstream. It is used to treat rheumatoid arthritis and Crohn's disease.
339
What are the two main side effects of drugs that bind and inhibit TNFa?
Immunosuppression and nerve demyelination
340
__________ can be completely humanized and generics can be produced.
Simple short peptides
341
___________ can possibly cause an immune reaction, biosimilars can be produced, and must be given parenterally.
Proteins
342
What is the drug Etanercept (Enbrel)?
Enbrel is a recombinant chimeric drug that is used to treat rheumatoid arthritis and psoriasis.
343
What is the MOA of Etanercept (Enbrel)?
Etanercept is a recombinant chimeric soluble protein drug that mimics the binding site of the TNFa receptor. TNFa binds to the fake receptor instead of binding to its real receptor therefore preventing leaking and degradation.
344
Is Etanercept a monoclonal antibody?
No
345
What is the drug Anakinra (Kineret)?
This drug targets interleukin-1 by mimicking the endogenous molecule called Interleukin-1 receptor antagonist which is a natural brake for IL-1 activities. It is used to treat rheumatoid arthritis.
346
What is the MOA of Anakinra (Kineret)?
This drug mimics interleukin-1 receptor antagonist. This stops the process of IL-1 promoting inflammation and breakdown of bone and cartilage.
347
Which of the following antibody is the safest for drug development purposes?
A. Ones that induce HAMA
B. Chimeric
C. Human
D. CDR-grafted antibody
C.
Human is safest. HAMA is the immune response mounted against a monoclonal antibody. Once HAMA happens, a patient cannot be treated with that drug again. Chimeric is 70% and CDR-grafted is humanized and is 90% human.
348
Pyroneuromab - what does it target and what is the source?
It targets the nervous system and its source is mouse antibodies.
349
Hectobacumab - what does it target and what is the source?
It targets bacteria and its source is human antibodies.
350
Old cancer drugs like DNA-alkylating agents and anti-proliferative agents are _______ specific. New anti-cancer drugs are able to distinguish between cancerous and non-cancerous cells thank to ___________.
NOT
Molecule biology
351
What are the two new generation anti-cancer agents?
1. Small molecule kinase inhibitors (ABL inhibitors, EGFR inhibitors, RAS pathway inhibitors)
2. Neutralizing antibodies (Herceptin, rituxan)
352
What are the 3 molecular targets specific for cancer cells?
1. Antigens encoded by oncogenic viruses (oncogenic meaning causes cancer)
2. Mutations of cancer-related genes
3. Translocation of proto-oncogenes (movement of gene from one place to another leading to cancer)
353
What is occurring when an individual has BCR-ABL due to translocation?
ABL is a kinase that is switched on to induce the production of myeloid cells. Sometimes, BCR can be placed in front of ABL and cause ABL to stay on and continue to tell the bone marrow to make myeloid cells. Eventually there are way too many myeloid cells which leads to chronic myeloid leukemia.
354
A patient has BCR-ABL. What disease do they likely have? What is another
name for the chromosome?
The patient has chronic myeloid leukemia. The other name for the chromosome is the Philadelphia chromosome.
355
Why is relapse for the treatment of CML and other cancers common in around 10% of patients?
Cancers are constantly mutating so even though a drug like GLEEVEC is specific for BCR-ABL tyrosine kinase and binds to the kinase to stop myeloid cell formation, after a while it can mutate and begin again.
356
What is the drug GLEEVEC (imatinib)?
This is a drug used to treat chronic myeloid leukemia by binding to the BCR-ABL tyrosine kinase through competition with its ATP binding site. It is a highly specific drug for kinases that are not crucial in adults.
357
What is the suffix for monoclonal antibodies?
-mab
358
Excessive EGFR/ERB-B signalling leads to __________.
Cancers. Normal functioning leads to growth, division, and survival.
359
What type of receptor is EGFR?
Tyrosine kinase receptor
360
What is the drug Gefitinib (Iressa)?
Iressa is a tyrosine kinase inhibitor that treats lung cancer in nonsmokers that are japanese and women. It only works if the cancer is due to a mutation in the kinase catalytic domain. When it binds, it stops intracellular signalling molecules from being phosphorylated and activated.
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What is the mutation in the kinase domain that allows Iressa to work in non-smokers?
Mutation of the 858 location.
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What drug was thought to work to inhibit angiogenesis by targeting VEGF and what drug is currently being used?
Endostatin was thought to work but it targeted cells in phases of remodeling and tissue repair. Now, Bevacizumab (Avastin) is used.
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What is the promise of finding drugs that can block VEGF in terms of cancer?
VEGF inhibitors would cause regression of microvessels to arrest tumor growth. It could normalize mature vasculature and inhibit neovascularization.
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Does Iressa work in lung cancer with a mutation in the extracellular domain?
No. Iressa only works in those with a mutation in the kinase domain
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Why is there no such thing as an EGF receptor blocker?
If a drug were to bind and inhibit EGFR it would result in severe skin rashes and it would block all EGFRs.
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What is angiogenesis?
This is the process of generating new blood vessels in tumors larger than 2mm. They need to do this as glucose and oxygen can no longer diffuse in.
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What is VEGF?
VEGF is the vascular endothelial growth factor.
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What is a drug discussed that targets VEGF?
Bevacizumab (Avastin)
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What are the adverse effects associated with VEGF inhibitors like Avastin?
Incomplete wound healing and serious GI perforations
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Drug Z binds to 12 different receptors. Does this information pertain to specificity or selectivity?
Selectivity- the number of receptors a drug binds to. If a drug binds to only 1 receptor, but at different organ types, it is selective.
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Drug Y binds to one receptor and causes many downstream effects. What is drug Y's relative specificity and selectivity?
High selectivity and low specificity. (binds to low number of receptors but produces a high amount of effects).
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What is Kd?
Kd is the concentration of drug which 50% of the receptors are bound. A lower Kd indicates a higher affinity while a high Kd indicates a lower affinity.
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A lower Kd indicates...
High affinity
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Drug R binds Drug s and prevent it from binding to its receptor. Which type of antagonist is Drug R?
Chemical antagonist
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Is a therapeutic index of 200 or 20 more safe?
A TI of 200 is more safe since it means that the therapeutic dose is far away from the toxic dose.
The larger the therapeutic index, the safe the drug is.
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What is complementary medicine?
It is used together with mainstream medicine
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Complementary and alternative medicine often lacks what type of evidence?
Safety and efficacy
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What does not rely on a drug's pharmacological action but requires analysis of a large number of polymorphisms?
Genome scanning approach
