Exam 4/ Final Flashcards
(267 cards)
1
Q
How do cells become cancerous?
A
Cancer begins when normal cells replicate in an uncontrolled manner. Cancer is more common in the older population due to their long life filled with replicative stress, toxins, infections, radiation, and more.
2
Q
What is the difference between a benign and malignant tumor?
A
A benign tumor has not left its original location of replication. These are easy to treat. Malignant tumors have broken from their original location and have spread. Hard to treat.
3
Q
What is an ‘in situ’ lesion?
A
When cells replicate in an uncontrolled manner, they form ‘in situ’ lesions that can be removed before they become invasive. These are common in the mouth, GIT, skin, and breasts. These lesions are the precursor for invasive carcinoma.
4
Q
Cancer is defined by what two things?
A
- Gain of proliferation signals
- Loss of cell death pathways
5
Q
How are cancer and EGFR related?
A
EGFR can undergo genetic changes (in the lungs), allowing it to be amplified. When the gene is amplified, more receptors are produced, which allows cell growth.
6
Q
What is the main target of cancer chemotherapy?
A
Different phases of the cell cycle.
7
Q
What protein is secreted in cells during the S-phase of the cell cycle?
A
Ki-67 protein is turned on during S-phase. It can be stained and will bind brown dye.
8
Q
What does High S-Phase Fraction mean?
A
This means that several cells are staining brown, identifying Ki-67. It can help indicate tumor severity.
9
Q
At what stage of life does your body have the largest number of cells in the S-phase?
A
We have a high proportion of cells in S-phase when we are sick, injuries, and during pregnancy.
10
Q
How were the first chemotherapy medications originally discovered?
A
It was found that mustard gas given to soldiers caused them to suffer from leukopenia. This caused their white blood cells to die, and they died from infection. It was discovered that mustard gas alkylates heme in red blood cells.
11
Q
What is the anti-neoplastic alkylating agent discussed during class?
A
Cyclophosphamide
12
Q
What is the MOA of cyclophosphamide?
A
This drug attaches a chemical group to DNA which stalls the replication fork causing DNA breakage. The cell notices the broken DNA, which sends damage signalling causing apoptosis of the cancer cell.
13
Q
What portion of the cell cycle is the drug cyclophosphamide targeting?
A
The S phase
14
Q
What is the significance of ATM kinase and protein p53?
A
DNA integrity is monitored by protein p53. This gives the cell the opportunity to stop replicating DNA that is damaged. When DNA signals damage, ATM kinase phosphorylates protein p53 causing it to go into the nucleus, acting as a transcription factor. The cell will now produce proteins that go to the mitochondria where channels are produced and proteins begin to eat the cell.
15
Q
What would happen in a tumor with a p53 mutation?
A
With a p53 mutation, alkylating drugs would have less action since it relies on the activation of protein p53.
16
Q
Do all cancer drugs cause immune suppression?
A
Yes.
17
Q
Do all cancer drugs induce nausea and vomiting?
A
Yes.
18
Q
What are the common side effects of alkylating agents?
A
Alkylating agents are toxic to bone marrow. This is because there is constant cell proliferation in bone marrow and alkylating agents target the S phase of the cell cycle.
19
Q
Cyclophosphamide is additionally used after an organ transplant. Why?
A
It suppresses the immune system giving the body a chance to accept the organ and not attack it.
20
Q
What are the pharmacokinetics of cyclophosphamide?
A
Injected Pro-drug that is activated by P450 proteins in the liver.
21
Q
Does cyclophosphamide conversion in the liver allow it to be a more specific cancer drug?
A
Makes it more effective but not more specific.
22
Q
If someone was taking a P450 inhibitor and cyclophosphamide, what would likely happen?
A
The drug would not be activated well in the liver making the drug less effective.
23
Q
What is another drug discussed in class that targets DNA?
A
Methotrexate
24
Q
What is the MOA of methotrexate?
A
Methotrexate resembles folic acid and inhibits the dihydrofolate reductase (DHFR) therefore blocking the synthesis of tetrahydrofolate (THF). It inhibits the production of nucleotides, making cells run out of the material they need to replicate DNA. It causes the cell to undergo apoptosis.
25
What is a unique thing that happens to methotrexate in the cell?
In the cell, methotrexate is cross-linked to polyglutamate derivatives. These derivatives are very active against DHFR, the target enzyme for this drug. The cross-linked version stays in the cell but the parent compound is not.
26
What is an antibiotic that can be used as an anti-neoplastic drug?
Doxorubicin. A product of the soil microbe Streptomyces.
27
What portion of the cell cycle does doxorubicin target?
G2 phase
28
What is the MOA of doxorubicin against cancer?
This drug binds to DNA, where it inhibits the topoisomerase II enzyme. This is the enzyme in the human body that reduces torsional stress during DNA unwinding. This causes the DNA to break into unuseable fragments.
29
What is FACS?
This is a measurement of DNA content versus the number of cells in a specific phase of the cell cycle.
30
What would a FACS look like after the administration of doxorubicin?
???
31
Doxorubicin works _________ and ________ replication.
During; after
32
Sarah is a 47-year-old female presenting with advanced-stage breast cancer that has a high S-phase fraction and has metastasized to the lymph nodes. What are her treatment options?
This is an unfortunate situation. A treatment option includes adjuvant TAC therapy after surgery to remove the primary tumor. TAC therapy includes Taxotere (docetaxel), Adriamycin (doxorubicin), and Cytoxan (cyclophosphamide).
33
What are the four phases of the cell cycle, and what happens in each?
G1 phase- cell increases in size, and cellular contents are doubled.
S phase- DNA replication
G2 phase- cell grows more, and organelles develop in preparation for cell division.
M phase- mitosis followed by cytokinesis. Formation of two identical daughter cells. (there is no nucleus here while ER and mitochondria are divided)
34
Do alkylating agents kill cells in the M phase of the cell cycle?
No.
35
What is the point of using TAC therapy?
TAC therapy is used to attack cancer cells in all different phases of the cell cycle.
36
How were the class of drugs called Taxols discovered?
Taxol was isolated from the bark of the western yew tree. It was found that it was really good at killing cancer cells.
37
What is the taxol drug discussed in class?
Paclitaxel
38
How was paclitaxel tested?
In order to test this drug, researchers used xenografts. Xenografts are when human cancer cells are introduced into a mouse. Mice are then made to be immune-compromised so their own body does not attack human cancer cells.
39
What is a phase 1 trial?
Phase 1 trials are about preventing toxicity, and testing is done on healthy individuals. This portion of the trial is not about the outcome of the drug.
40
What is a phase 2 trial?
Phase 2 trial asks about efficacy, dosing, effects, and different responses based on BMI, genetics, sex differences, etc. There are no placebos given in phase 2 trials. Given to sick individuals.
41
What is a phase 3 trial?
Phase 3 trials can use placebos.
42
What is the MOA of paclitaxel?
During mitosis, tubulin must polymerize, and the microtubules must be disassembled for mitosis to proceed. Paclitaxel promotes tubulin polymerization and blocks the disassembly of microtubules leaving the cell stuck in mitosis.
43
What would a FACS look like after the administration of paclitaxel?
44
What are the common side effects of anti-mitotic drugs like paclitaxel?
These drugs induce common symptoms of chemotherapy. Additionally, they can trigger neuropathy that presents as weakness, numbness, and tingling.
45
What is a graphical representation of chemotherapy treatment against non-resistant cancer?
46
What is the graphical representation of chemotherapy treatment against resistance cancer?
47
What would be one reason for cancer becoming resistant?
If cancer cells express a large number of p-glycoproteins, doxorubicin cannot be used to treat cancer. This protein will efflux the drug out of the cell.
48
What are the 5 main ways that we target cancer with drug therapy?
1. Chemotherapy
2. Kinase receptors
3. Nuclear receptors
4. Immune targeting
5. Others
49
How is EGFR involved in cancer proliferation?
Epidermal growth factor (EGF) binds to the tyrosine-kinase receptor called EGFR. EGF binding to its receptor increases proliferation, decreases cell death and makes cells move. Cetuximab is a monoclonal antibody that binds the extracellular domain on EGFR, preventing EGF from binding.
50
What drugs are used when cancer is being stimulated by EGFR?
Cetuximab and chemotherapy together induces apoptosis more effectively.
51
What is a typical cancer that cetuximab is used for?
Lung cancer
52
What is a specific anti-TNF antibody used to combat cancer?
Adalimumab (Humira) is an antibody that binds to alpha-TNF and neutralises it. With TNFR being neutralized, the transcription of many genes in inflammation, survival, and apoptosis is halted.
53
Why is TNF-directed therapy an improvement over methotrexate?
TNF-directed therapy is much more specific than methotrexate. Methotrexate stops the production of nucleotides for all cells in the body while TNF therapy specifically binds TNF and stops its action.
54
Why does cancer still replicate even after EGFR is inhibited?
MET is another tyrosine kinase receptor-like EGFR. It can provide growth signals once EGFR is disabled.
55
How does chronic myeloid leukemia (CML) begin?
Some chromosomes have the ability to break more than others, specifically chromosomes 9 and 22. The break between these two chromosomes creates a perfect fusion forming a new fusion protein called Bcr-Abl. Bcr and Abl are genes. The new 9-22 fusion creates the new signalling protein called Bcr-Abl. Abl is an intracellular tyrosine kinase that is now signalling out of control. Now together, Bcr-Abl protein promotes growth and prevents cell death. This causes chronic myeloid (bone marrow) leukemia.
56
What are the risk factors for chronic myeloid leukemia?
Age, male, and DNA damage
57
What can Bcr-Abl be stopped by?
A kinase inhibitor called Imatinib.
58
What is the drug Imatinib used for?
This drug is a kinase inhibitor that blocks Bcr-Abl intracellular tyrosine kinase.
59
What is the drug Tamoxifen used for?
This type 1 nuclear receptor steroid receptor antagonist binds and blocks the estrogen receptor. This prevents estrogen from going into the nucleus to act on protein expression. Tamoxifen is typically used in estrogen-dependent breast cancer.
60
What are cancer cell checkpoints?
When cancer initially breaks out of its original location, immune cells are sent out to destroy them. Cancer cells actually have an immune checkpoint on them that basically disguises their identity. This stops the immune system from recognizing cancer.
61
What is an immune checkpoint inhibitor?
This is a type of drug that stops cancer cells from becoming invisible to the immune system.
62
What is the immune checkpoint inhibitor discussed in class?
Nivolumab
63
What is the basic physiology of stomach acid secretions?
Parietal cells within the lining of the stomach secrete stomach acid. Before being triggered, they are just chilling there with their mitochondria and proton pumps. It has several important receptors triggering its release of H+ ions, like muscarinic and histamine (H2) receptors. Some sort of outside signalling will trigger the vagus nerve to produce acetylcholine (ACh) that will bind to the muscarinic receptor. ACh also binds to histamine receptors which trigger them to release histamine that will bind to the H2 receptor in parietal cells. When histamine binds to the H2 receptor, the parietal cell totally changes shape. New canaliculus acid channels are formed and proton pumps will translocate to line those channels. Now the proton pumps pump H+ ions into the stomach.
64
CASE STUDY: 72-year-old woman experiences acid indigestion after a meal. She has taken antacids frequently for 30 years. She now has acute pain beneath the sternum and blood streaked-stools. Antiacids are no longer effective. She needs more powerful therapy. What would that entail?
We could give her omeprazole.
65
What is special about the proton pump in the parietal cells?
They are ATPase pumps that require a lot of energy. This is why parietal cells have a lot of mitochondria.
66
What is a proton-pump inhibitor (PPI)?
This is a type of drug that eventually blocks the proton-pumps from releasing H+ ions into the stomach.
67
What is the specific PPI discussed during class?
Omeprazole.
68
What are the unique characteristics of PPIs?
PPIs need an acidic environment to be activated but are not absorbed from the stomach. Additionally, PPIs do not work instantly, and concentration needs to build up. This is why PPIs must be taken BEFORE a meal. It is also an irreversible drug that binds to the proton pump and permanently inhibits it.
69
What type of drug is Omeprazole?
This is a proton-pump inhibitor. It is a weak base that is absorbed in the intestines.
70
What are the pharmacokinetics of omeprazole?
Packaged into acid-resistant formulation so it can be better absorbed in intestines (unstable in low pH). It is taken into circulation, where it accumulates in parietal cells due to its love for the proton pump and the acidic state of the parietal cell. The drug is inactive until parietal cells begin secreting H+ ions, where it then undergoes a chemical change. This change allows omeprazole to cross-link to the proton pump and inhibit its actions.
71
What type of volume of distribution does omeprazole have?
A low Vd of 0.3 kg/L means it does not readily enter peripheral tissues and likes to stay in circulation. A low Vd means it also has a short half-life.
72
If PPIs bind irreversibly to proton pumps, why do the drugs only last 24-48 hours?
The turnover rate of proton pumps is really high, just like the rest of the things in the stomach. Once the proton pump is degraded again, the medication is no longer viable.
73
What is the MOA of omeprazole?
Irreversibly binds and cross-links the proton-pump stopping its H+/K+ secretions into the stomach.
74
What are some of the consequences of raising the pH of the stomach?
The body cannot take up nutrients as readily. Hypergastremia is also likely, which can cause cancer. Gastric bacterial overgrowth of C. Diff can also occur with PPI use.
75
CASE STUDY: The 72-year-old woman returned 2 weeks later and said the PPI was not working. After eating, her stomach still hurt, so she decided to start taking antacids in the evening. What happened?
Since PPIs need an acidic environment to be activated, taking an antiacid will not allow the drug to be activated which would stop it from producing its proper effects.
76
What are Helicobacter pylori bacteria?
This is a type of bacteria that can cause peptic ulcers. It can be treated with antibiotics combined with a PPI. Antibiotics commonly used are metronidazole, clarithromycin, or amoxicillin. Metronidazole is used because it is activated in anaerobic environments. Once the drug is reduced to its active toxic radical, it will attack the bacterial H. pylori DNA. This interferes with replication and causes DNA fragmentation. Clarithromycin targets the 50s subunit of bacterial RNA, and amoxicillin targets the PBP preventing cell wall formation.
77
CASE STUDY: Erika is a 24-year-old woman who is flying on a vacation in Montana. The trip will require a flight in a small airplane. She is worried about motion sickness as she sometimes gets carsick, even under normal highway conditions. What type of therapy might she consider?
Dramamine
78
How do nausea and vomiting work on a basic level?
It appears that vomiting associated with pregnancy or motion sickness functions through a histamine H1 receptor and muscarinic cholinergic receptor.
79
What is Dramamine (Diphenhydramine)
This is an H1 receptor inverse agonist. Additionally, it has anticholinergic effects (inhibits muscarinic acetylcholine receptors). Dramamine is packaged with 8-chlorotheophylline which acts like a stimulant.
80
CASE STUDY: 5 year old has a poor diet of chicken nuggets, fries, and cookies. He remains constipated for days at a time and even has experienced nausea as a result. What is the treatment?
Miralax
81
What type of drug is Miralax?
This is an osmotic agent. Other osmotic agents include non-digestible sugars and milk of magnesia.
82
What is the MOA of Miralax?
Miralax is polyethylene glycol. It is a non-digestible fiber that is poorly absorbed by the GIT. These substances also pull in water to the GIT causing a peristaltic effect.
83
CASE STUDY: Patricia is a 34-year-old woman who travelled to Mexico, drank unbottled water, and ate from street vendors. She has now been experiencing diarrhea for 12 hours. What are her treatment options?
Imodium (Loperamide)
84
What is the MOA of loperamide (Imodium)?
This drug binds to opioid receptors in the gut. By doing this, it reduces peristalsis and increases intestinal transit time.
85
Does Loperamide (Imodium) cross the blood-brain barrier?
It gets into the brain at the correct doses and is immediately effluxed by p-glycoproteins.
86
What would happen to the body if someone was on an additional drug inhibiting p-glycoproteins while taking Imodium?
Imodium would be able to cross the blood-brain barrier and stay there. It would cause constipation similar to what opioid users experience.
87
The circulatory system is composed of what two components?
1. Systemic circulation- moves blood from the heart to the rest of the tissues. It then returns deoxygenated blood back to the heart.
2. Pulmonary circulation- moves blood between the heart and the lungs. It transports deoxygenated blood to the lungs, where it gets oxygenated and then goes back to the heart.
88
What is blood pressure?
It is the pressure exerted by the blood against the blood vessel walls. It is needed to ensure steady blood perfusion to the tissues.
89
What are the two main components of blood pressure?
Cardiac output (heart rate x stroke volume) and peripheral resistance
90
What is stroke volume?
The amount of blood ejected from the heart in each pump from the left ventricle.
91
What are the ranges for blood pressure stages?
92
What is considered normal blood pressure?
Less than 120/ <80 (AND)
93
What is considered elevated/ pre-hypertensive blood pressure
120-129/ <80 (AND)
94
What is considered stage 1 hypertension?
130-139/ 80-89 (OR)
95
What is considered stage 2 hypertension?
140
96
What is a hypertensive crisis where emergency care is needed?
180
97
What is primary/essential hypertension?
This is when patients have no specific cause for the hypertension.
98
What is secondary hypertension?
This is when patients have a specific cause of hypertension. Could be caused by renal disease or primary aldosteronism. Usually occurring issues in kidneys, arteries, heart, or endocrine system.
99
What is systolic blood pressure?
This is the pressure that blood is exerting against the artery walls when the heart is beating (contraction) and pumping blood out.
100
What is diastolic blood pressure?
This is the pressure that blood exerts against the artery walls when the heart is at rest (relaxation).
101
Blood pressure can change all the time based on the most random things. How many consistent measurements of hypertension need to be collected before it can be diagnosed?
Three different elevated readings are needed to be diagnosed.
102
What are hypertension's general signs and symptoms, even though it is typically asymptomatic?
Headaches in the morning, ringing in ears, unexplained dizziness, spontaneous nosebleeds, fatigue, nausea, vomiting, blurred vision, irregular heart beat, and flushing of the face.
103
Is elevated systolic or diastolic blood pressure worse?
Having hight diastolic pressure is worse because even when the heart is relaxed, pressure is still to high.
104
What are the rates of hypertension in males and females before menopause?
1 in 4 males
1 in 5 females
105
What is the WHO rule of 1/3s?
1/3 of all adults suffer from hypertension. 1/3 of those adults do not know they have hypertension. 1/3 of adults treating their hypertension cannot keep it under 140/90.
106
What are some of the different causes of hypertension?
Genetics and family history, age and gender, obesity, dietary habits, physical inactivity, drug-induced (NSAIDs, cyclosporine, hormonal contraceptives, nicotine, smoking), and psychosocial stress.
107
What are the complications associated with hypertension?
CVD, CBD, renal disease, and retinopathy
108
Why are men more likely to get hypertension than pre-menopausal women?
Testosterone is known to increase RAAS, while estrogen does the opposite. The goal of RAAS is to control long-term blood pressure change.
109
There are short-term and long-term ways the body regulates blood pressure. What are the short-term methods?
Regulating cardiac output and peripheral resistance. Cardiac output is regulated by the sympathetic and parasympathetic nervous system. (Part of the autonomic nervous system, which is part of the peripheral nervous system). Peripheral resistance is regulated by baroreceptor and chemoreceptors reflexes.
110
What substrate stimulates the alpha and beta-adrenergic receptors in the sympathetic nervous system?
Catecholamines (epinephrine, NE, dopamine) stimulate beta-adrenergic receptors in the heart and alpha-adrenergic receptors in the vessels. When these receptors are stimulated, blood pressure will increase.
111
What are the long-term methods of regulating blood pressure in the body?
Regulating blood volume through the RAAS and anti-diuretic hormone (AHD)/ vasopressin.
112
What are the 4 drug targets for hypertension?
1. Target sodium reabsoprtion in the kidneys
2. Target RAAS by blocking angiotensin II to stop vasoconstriction.
3. Beta-adrenergic receptors in the heart
4. Alpha-adrenergic receptors in vessels
113
What are the 3 drug classes used to treat hypertension?
1. Diuretics (3 types)
2. Drugs that interfere with RAAS (4 types)
3. Drugs that reduce CO or PR (2 types)`
114
What are the 3 diuretics talked about in class?
1. Thiazide diuretics
2. Loop diuretics
3. K-sparing diuretics
115
Where do diuretics work?
They work in different spots in the kidney.
116
What are the two main types of thiazide diuretics?
Chlorothiazide and Hydrochlorothiazide
117
What is the MOA of diuretics?
All diuretics work in the nephrons of the kidneys (at different spots) and inhibit sodium reabsoprtion. This then increases urinary sodium and water excretion.
118
Where do loop diuretics work in the nephron?
Loop diuretics work on the loop of Hendley, where around 25% of sodium reabsorption occurs.
119
What is the loop diuretic discussed in class?
Furosemide
120
Where do thiazide diuretics work in the nephron?
Thiazide diuretics work on the distal convoluted tubule where 50% of sodium is typically absorbed.
121
Where do K+-sparing diuretics work in the nephron?
Potassium-sparing diuretics target the collecting ducts where 1-2% of sodium is typically reabsorbed.
122
What are the 3 K+-sparing diuretics discussed in class?
Spironolactone, Amiloride, and Triamterene
123
What is the efficacy of the different diuretics?
Loops diuretics > Thiazide diuretics > K+ sparing diuretics
124
What type of diuretic is used to treat low or moderate hypertension?
Thiazide diuretics
125
What are the main adverse effects of diuretics?
Possible kidney damage, hypovolemia (too low BP), electrolyte imbalance, dizziness, and hypokalemia (K+ more important than Na+)
126
What are the main therapeutic considerations for diuretics?
First-line treatment for low or moderate hypertension due to its relative safety and efficacy.
127
What is the weakest diuretic?
K+-sparing diuretics
128
What are the 4 types of drugs that interfere with RAAS?
1. ACE inhibitors
2. Angiotensin II receptor antagonists
3. Aldosterone antagonists
4. Direct renin inhibitor
129
What is the RAAS?
The kidney secretes renin. Renin functions to convert angiotensinogen (secreted by the liver) to angiotensin 1 (inactive). Then the enzyme angiotensin-converting enzyme (ACE) from the lung converts angiotensin 1 to angiotensin 2. Angiotensin 2 is a vasoactive peptide causing vasoconstriction. Angiotensin 2 works short-term to increase blood pressure. Angiotensin 2 stimulates the adrenal glands to secrete aldosterone. Aldosterone promotes water reabsoprtion.
130
Who is the main player of the RAAS?
Angiotensin 2
131
What are the two types of classes of drugs used to target the RAAS?
1. Angiotensin-receptor blocks (ARBs)
AND
2. Angiotensin-converting enzyme inhibitors (ACEi)
(these drugs increase blood potassium, so they are typically paired with diuretics)
132
What are the 2 ACE inhibitors discussed during class?
Captopril and Enalapril
133
What is the site of action for ACE inhibitors?
Angiotensin Converting Enzyme (ACE). This is the enzyme from the lung that converts inactive angiotensin 1 to active angiotensin 2.
134
What is the MOA for ACE inhibitors?
ACE inhibitors inhibit the ACE enzyme. This stops the conversion of ang 1 to active ang 2. Without ang 2, there is less vasoconstriction and a decrease in aldosterone, which stops water reabsoprtion in the kidneys. This causes a decrease in blood pressure.
135
When are ACE inhibitors typically used?
They are used for hypertension, heart failure, and hypertensive patients with RENAL FAILURE.
136
What are the common side effects of ACE inhibitors?
Fatigue, hypotension, dry cough, angioedema, and hyperkalemia (can cause cardiac arrest).
137
What is the site of action of angiotensin receptor blockers (ARBs)?
Act on the angiotensin 2 receptor.
138
What is the MOA of angiotensin receptor blockers (ARBs)?
They block the angiotensin 2 receptor, which blocks angiotensin 2 from binding. This lack of binding causes vasorelaxation, which decreases blood pressure.
139
What are angiotensin receptor blockers (ARBs) used for?
Hypertension, heart failure, and post MI
140
What were the three angiotensin receptor blockers (ARBs) discussed in class?
Valsartan, Losartan, and Irbesartan
141
What are the common side effects of angiotensin receptor blockers (ARBs)?
Dizziness, headache, faintness upon rising, vomiting, coughing (less common than ACE), and hyperkalemia.
142
What are the two types of drug classes used to reduce CO or PR in reducing hypertension?
1. Sympathetic nervous system depressants (alpha and beta blockers)
2. Direct vasodilators (calcium channels blockers and nitrates)
143
What are the main differences between the sympathetic and parasympathetic nervous system?
The sympathetic nervous system is activated by neurotransmitters epinephrine and NE, increasing heart rate, blood pressure, breathing rate, and pupil size. The receptors we are discussing here are alpha and beta-adrenergic receptors. Parasympathetic is your rest and digest peaceful state.
144
Where are the different types of alpha-adrenergic receptors located?
Alpha-1 is located in smooth muscle cells, specifically, here we are interested in the vessels. Its activation will cause vasoconstriction, increased PR, and an increase in blood pressure.
145
Where are the different beta-adrenergic receptors located?
Beta-1 adrenergic receptors are located in the heart. Beta 2 is in smooth muscle, and beta 3 is in adipose tissue. We are concerned with beta-1 in the heart. The activation of beta-1 in the heart increases heart rate, myocardial contractility, and renin secretion.
146
What do beta-blockers alter?
Cardiac output
147
What is the site of action for beta-blockers?
Mainly in the heart, but propanolol would cause vasoconstriction of bronchials.
148
What is the MOA of beta-blockers?
Beta-blockers block the beta-adrenergic receptor from being activated by E or NE. With no stimulation, the heart rate will decrease, which decreases cardiac output, which decreases blood pressure.
149
What is the main use of beta-blockers?
Useful in treating hypertension with pre-existing conditions like previous MI or angina pectoris (chest pain).
150
What are the common side effects of beta-blockers?
Can cause bradycardia, fatigue, impotence, and cold extremities.
151
What types of conditions are beta-blockers never prescribed to?
Those with asthma, diabetes, and bradycardia.
152
What are alpha 1 blockers altering in the body?
Peripheal resistance of vessels.
153
What are the 3 alpha-1 blockers discussed during class?
Prazosin, Terazosin, and Dexazosin
154
What is the site of action of alpha-1 blockers?
Mainly the blood vessels.
155
What is the MOA of alpha-1 blockers?
Block the alpha-1 adrenergic receptor in smooth muscle. Without stimulation by E or NE, vascular muscular relaxation will occur, which reduces peripheral resistance decreasing blood pressure.
156
What are common side effects of alpha-1 blockers?
Nausea, drowsiness, postural hypertension, and 1st dose syncope (rapid fall in BP from sitting to standing).
157
When can alpha-1 blockers never be prescribed?
Those will hypersensitivity to these drugs.
158
When would alpha-1 blockers be used?
Useful in diabetes, asthma, and mild to moderate hypertension. Often paired with a diuretic.
159
Why can calcium channel blockers be used to reduce CO and/or PR?
Calcium is required for muscles in the vessels to contract and vasoconstrict. When calcium channels are blocked, muscle can't contract and vasodilation occurs, decreasing blood pressure.
160
What are the two cardioselective calcium channel blockers discussed in class?
Deltiazem and Verpamil
161
What are the two vasoselective calcium channel blockers discussed during class?
Nifidipine and Amlodipine
162
What is the site of action of calcium channel blockers (CCBs)?
They act on vascular smooth muscle (heart or vessel depending on drug)
163
What is the MOA of calcium channel blockers (CCBs)?
They block the calcium channels in vascular smooth muscle. This causes vascular muscle relaxation. Vasodilation occurs as well as reduced cardiac muscle contraction. Overall decreases peripheral resistance.
164
What are the therapeutic considerations for prescribing calcium channel blockers?
Prescribed for angina, arrhythmia, and hypertension.
165
What are the common side effects of calcium channel blockers (CCBs)?
Flushing, headaches, dizziness, nausea, heart palpitations (action potentials changing), and bradycardia.
166
When would calcium channel blockers not be prescribed?
Cannot be prescribed for myocardial infarctions and heart failure.
167
What type of antihypertensive drug can be given to those with heart failure?
ACE inhibitors and diuretics
168
What type of antihypertensive drug can be given to those with myocardial infarction?
ACE inhibitors and beta-blockers
169
What type of antihypertensive drug can be given to those with renal insufficiency?
ACE inhibitors
170
What type of antihypertensive drug can be given to those with angina?
Beta-blockers and calcium channel blockers
171
What type of antihypertensive drug can be given to those with asthma?
Alpha-1 blockers & Calcium channel blockers (NO BETA BLOCKERS)
172
What type of antihypertensive drug can be given to those with diabetes?
ACE inhibitor (NO BETA BLOCKERS)
173
What is the composition of blood?
Blood contains 55% plasma, 4% WBC (leukocytes), platelets (thrombocytes), and 41% RBC (erythrocyte).
174
What is coagulation?
This is the process involving platelets, coagulation factors, and fibrinolytic systems to change the state from liquid to gel/solid form. Coagulation can be initiated by (1) extrinsic stimulation (tissue damage) or (2) intrinsic stimulation (injury to endothelial lining of blood vessel)
175
What is a thrombus?
An abnormal clot that forms in the vessel and remains there.
176
What is an emboli?
A clot that travels from the site where it was formed to another location in the body.
177
What is thrombosis?
This is when a thrombus is blocking an artery or vessel.
178
What is an embolism?
An embolism is a thrombus that dislocates and then blocks an artery or vessel in the lung.
179
What is deep vein thrombosis (DVT)?
Blood clot develops in the veins. Can be found in the thigh, lower leg, pelvis, and arm
180
What is a pulmonary embolism (PE)?
Blockage in one of the lung arteries.
181
What is thrombocytopenia?
Low platelet count. Normal platelet count is 150k to 450k/ mL of blood.
182
What is thrombocytosis?
Abnormal high count of platelets.
183
What are the 4 stages of blood coagulation?
1. Constriction of blood vessel- injury stimulation to restrict additional blood loss.
2. Formation of temporary platelet plug- Collagen from exposed blood vessels activates platelets in the blood flowing past injury. The platelets then aggregate together to form a temporary plug, stopping bleeding.
3. Activation of the coagulation cascade- Platelets change shape from round to spiny, which further stimulates proteins from the platelets like ADP and TXA2. These proteins further enhance platelet aggregation.
4. Formation of fibrin plug/final clot- Further platelet aggregation cascade brings in final material called fibrin to form the final clot.
184
What are the 3 coagulation pathways?
A. Factor X- an enzyme produced in the liver that requires vitamin K for its synthesis. Needs to be activated
B. Factor II/ Prothrombin- a protein produced by the liver. Activated factor X activates prothrombin to thrombin.
C. Fibrinogen- Glycoprotein completely made in the liver that is circulating in the blood. During injury, it is converted to active fibrin by thrombin. Together with platelets, they plug the wound site.
185
What are the 3 drug classes acting on coagulation pathways?
A. Antiplatelets
B. Anticoagulants
C. Fibrinolytic agents (thrombolytics)
186
What are antiplatelets/ blood thinners?
These are drugs that inhibit platelet aggregation and reduce the chance of blood clotting. Used preventatively for those at high risk for MI and stroke.
187
What are the common antiplatelets/ blood thinners discussed in class?
Aspirin and Clopidogrel
188
What is the MOA of antiplatelet aspirin?
Aspirin irreversibly inhibits the enzyme cyclo-oxygenase (COX-1), which is required to make the precursors of thromboxane within platelets. Inhibition reduces thromboxane synthesis, which is needed for platelet aggregation. Aspirin is 150 times more potent of an inhibitor for COX-1 than COX-2 (inflammation one). That is why a baby aspirin dose of 80-100 mg is given as an antiplatelet. Larger doses would begin to inhibit inflammation.
189
What is the MOA of the antiplatelet drug Clopidogrel?
Inhibits the binding of ADP to its platelet receptors. Without this binding, the platelets cannot change into a spiny shape which inhibits the aggregation of more platelets and the release of thromboxane A2.
190
What are the main therapeutic considerations for the use of antiplatelets/ blood thinners?
Used in patients with high risk of MI and stroke.
191
What are the common side effects of antiplatelets/ blood thinners?
Bruise easily, longer bleeding times, upset stomach, heavy menstruation, and long nose bleed.
192
What is Abciximab?
This is a drug that inhibits platelet aggregation. It does this by binding the glycoprotein receptor on human platelets and inhibits the binding of fibrinogen, therefore, inhibiting platelet aggregation.
193
What are anticoagulant drugs?
These drugs are known as vitamin K antagonists.
194
What is the oral anticoagulant drug discussed in class?
Warfarin
195
What is the indirect parenteral anticoagulant discussed in class?
Heparin
196
What are the two direct parenteral anticoagulants discussed in class?
Hirudin and Lepirudin
197
What is the MOA of Warfarin?
The oxidized form of vitamin K is reduced to become active by an enzyme called vitamin K epoxide reductase. The active form of vitamin K will activate the inactive clotting factors II, VII, IX, and X. Warfarin inhibits the function of the enzyme vitamin K epoxide reductase in the liver. This leads to the depletion of reduced forms of vitamin K that should be activating clotting factors. Thus, this inhibits the synthesis of active clotting factors.
198
Does warfarin work fast or slow?
It works slowly because it has no effect on already synthesized clotting factors, only the ones that will eventually be activated by vitamin K.
199
What are the main therapeutic considerations of warfarin?
Used in all thrombosis related events like DVT or PE after a heparin treatment.
200
What are the common side effects of warfarin?
Severe bleeding is possible due to a narrow therapeutic window, adverse reactions with alcohol, NSAIDs, and acetaminophen, has numerous reactions with vitamin K-containing foods.
201
How long does it typically take for a patient to see the benefits of warfarin?
It can take 2-3 days to see a benefit, while prothrombin time (PT) is also monitored. A longer PT means the drug is working.
202
What are the factors that contribute to different dosing requirements for warfarin?
1. Vitamin K absorption and intake
2. Warfarin clearance
3. Genetic polymorphisms
203
What is the MOA of the indirect thrombin inhibitor, Heparin?
This drug indirectly inhibits thrombin activity by increasing the activity of antithrombin. Antithrombin is an endogenous anticoagulant that inhibits thrombin and factor X release, therefore, blocking the coagulation cascade.
204
Why is heparin given IV?
Heparin is not absorbed in the gut, so needs to enter directly into circulation. Not given intramuscularly either!
205
What are the main therapeutic considerations for heparin?
Has rapid onset of action and is therefore used to initiate immediate anticoagulation in PE, DVT, or MI.
206
What are the common side effects of heparin?
Bleeding, allergic reactions, long-term use is associated with osteoporosis and heparin-induced thrombocytopenia.
207
What are the two direct thrombin inhibitors discussed in class?
Hirudin and Lepirudin
208
What is the MOA of direct thrombin inhibitors?
Directly bind to thrombin and inhibit its actions. This stops the conversion of fibrinogen to fibrin. This stops final clot from being produced.
209
What is the difference between indirect thrombin inhibitors (heparin) and direct thrombin inhibitors (hirudin and lepirudin)?
Direct thrombin inhibitors do not cause thrombocytopenia like heparin does in some users. Both drugs work fast.
210
What are fibrolytic agents/ thrombolytics?
A protein present in the blood called plasminogen (fibrinolysin) is inactive until it is converted to plasmin by a plasminogen activator. Plasmin lysis fibrin clots.
211
What is the fibrolytic agent/ thrombolytic discussed in class?
Streptokinase
212
What is the MOA of streptokinase?
This thrombolytic drug activates the conversion of plasminogen to plasmin which lyses the clot.
213
When would streptokinase be used?
Given after a clot has already formed. Can be given 3 hours after stroke and 12-24 hours after heart attack. The sooner the better though.
214
What are the adverse effects of thrombolytics like streptokinase?
Major bleeding
215
What is the reversal agent for a parenteral antagonist like heparin?
Protamine sulfate
216
What is the reversal agent for vitamin K antagonists like warfarin?
Vitamin K
217
What is the reversal agent for an antiplatelet agents like aspirin or clopidogrel?
Activated platelets
218
What is the reversal agent for fibrinolytic agents like streptokinase?
Aminocaproic acid
219
An oncologist is considering two tumors of the same type that came from different patients. Tumor A has an S phase fraction of 38%, while tumor B has an S phase fraction of 12%. What can the oncologist conclude from this finding?
A. Tumor A is less likely to stain positively (brown) for the marker Ki-67 than tumor B.
B. Tumor A will have a smaller need for dNTPs than tumor B.
C. Tumor A would respond less well to chemotherapy than tumor B.
D. Tumor A would have more DNA replication forks than tumor B.
D. Tumor A would have more DNA replication forks than Tumor B.
220
A subset of genes are often mutated in cancer. Specifically, some tumors make a normal (wild-type) version of the p53 protein, while other tumors express an inactive, mutated form of p53. How would you expect tumors making a mutated form of p53 to be different from those expressing wild-type p53 with regard to the response of cancer cells to standard chemotherapy?
A. Chemotherapy responses would be the same whether p53 was wild-type or mutated.
B. In tumors expressing mutated p53, chemotherapy would directly damage the DNA more.
C. In tumors expressing mutated p53, less cytochrome c would be in the cytoplasm after chemotherapy.
D. In tumors expressing mutated p53, more cytochrome c would be in the cytoplasm after chemotherapy
C. In tumors expressing mutated p53, less cytochrome c would be in the cytoplasm after chemotherapy. If p53 is missing, cancer cells will not die.
221
Cyclophosphamide is a cancer chemotherapy agent that is highly toxic. What is the best explanation for immune suppression caused by cyclophosphamide?
A. Cancer makes people very tired, and their immune cells are dying anyway
B. Immune cells are killed by cyclophosphamide when the immune cells proliferate
C. Immune cells are sensitive to cyclophosphamide because they are unable to grow
D. Immune cells have an internal resistance mechanism to cyclophosphamide
B. Immune cells are killed by cyclophosphamide when the immune cells proliferate.
222
If a tumor contained a high fraction of cells in S phase, which of the following drug mechanisms would target that population of cells?
A. Inhibiting entry into the cell cycle
B. Inhibiting topoisomerase 2
C. Disrupting microtubule depolymerization
D. Inhibiting cytochrome P450 proteins
B. Inhibiting topoisomerase 2
223
Some important early-stage testing of cancer drugs (and other kinds of drugs) is in mouse xenografts. How does one make a mouse xenograft?
A. Grow a colony of mice and select those that form tumors
B. Give the mice a carcinogen and select ones in which tumors form
C. Inject mice with mouse-derived cancer cells, which form a tumor
D. Inject mice with cells from another species, like humans
D. Inject mice with cells from another species like humans
224
Which of the following best represents the side effects of paclitaxel?
A. Paclitaxel causes nervous system pain (neuropathy) by altering signaling
B. Paclitaxel causes few side effects because most cells do not use the protein that it inhibits
C. Paclitaxel is used to treat arthritis and other inflammatory diseases
D. Paclitaxel is a pro-drug, so it does not work in people with liver damage
A. Paclitaxel causes nervous system pain (not really by altering signal though)
225
A drug company has developed a new product that has promise for helping people to quit smoking. It works well when administered to rats. You want to see if people are able to tolerate it without experiencing serious side effects, and you recruit 3 people for a control group and 7 people for an experimental group. It causes side effects, so you decide to return to the rats and test lower doses. What is this type of rat experiment called?
A. Pre-clinical testing
B. A phase 1 clinical trial
C. A phase 2 clinical trial
D. Phase 3 market research
A. Pre-clinical testing
226
A patient with lymphoma is treated with a classic regimen for the disease that includes doxorubicin and paclitaxel. It works well and the cancer is gone for 4 years. Unfortunately, at that point, the tumor begins growing again and does not respond to the same treatment. What is a likely reason that the treatment does not work this time? What is a protein that might have changed to produce this effect?
The treatment is likely not working due to its development of drug resistance. A protein like p-glycoprotein that effluxes drugs like doxorubicin could produce this effect.
227
Estrogen receptor is produced (expressed) by breast cancer cells. If you were to treat breast cancer cells with an estrogen receptor inhibitor, what would be the result?
A. The receptor would no longer phosphorylate proteins
B. The receptor would remain inert in the cytoplasm
C. The receptor would be unable to transport ions across a membrane
D. The receptor would remain bound to inhibitory G proteins
B. The receptor would remain inert in the cytoplasm.
228
11. In lung cancer, combining an EGFR inhibitor with chemotherapy can improve the effectiveness of the chemotherapy. What is the reason for this effect?
A. An EGFR inhibitor turns off a survival signal, increasing cell killing
B. An EGFR inhibitor makes the cells grow, increasing cell killing
C. EGFR is a DNA repair protein, so inhibiting EGFR causes DNA damage
D. EGFR pumps drugs out of the cell, so inhibiting it decreases drug efflux
A. An EGFR inhibitor turns off a survival signal, increasing cell killing.
229
Describe the limitations of taking antacids to resolve acid indigestion.
Antiacids have a short duration of action around (30-60 min), while a PPI works for 24-48 hours.
230
If you worked for a company that developed a high affinity partial agonist for the H2 histamine receptor, what would be the likely effects of it (a) without eating, and (b) after a meal?
A. Modest increase in acid production
B. No further elevation in stomach acid
231
Some patients experience nausea after some medical procedures. Sometimes antihistamines are used to relieve that response. Do you think that diphenhydramine/Benadryl or loratadine/Claritin would be more effective for relieving those symptoms? Why?
Diphenhydramine is indicated for H1 receptors involved in nausea and vomiting. Claritin works on H2 receptors which are not associated with nausea and vomiting.
232
What is the role of metronidazole in a treatment regimen for peptic ulcer disease?
A. To deplete nucleotides in all types of bacteria
B. To damage DNA in anaerobic bacteria
C. To damage DNA in aerobic bacteria
D. To block acid release into the stomach while the tissue heals
B. To damage DNA in anaerobic bacteria
233
In combination therapy for peptic ulcer disease, what is the function of clarithromycin?
A. Damaging DNA
B. Inhibiting protein synthesis
C. Inhibiting proteoglycan cross-linking
D. Inhibiting the histamine H2 receptor
B. Inhibit protein synthesis
234
Proton pump inhibitors are taken orally in pill form, but somehow find their way to cells in the stomach where they inhibit their target. Describe the path that a proton pump inhibitor takes to get to its site of action and inhibit its target protein. Feel free to add diagrams if that would help.
PPI, like omeprazole, is taken orally in an acid-resistant formulation as it is unstable in that environment and needs to be absorbed in the GIT. Once the drug is absorbed, it makes its way through the body, where it eventually ends up in parietal cells in the stomach due to its love for acidic proton pumps. Once in parietal cells, proton pumps must start actively producing H+ ions in order to activate omeprazole. Once activated, the drug cross-links the proton pump and irreversibly inhibits it.
235
What is a tyrosine kinase receptor?
Span the plasma membrane. Has two distinct domains; the extracellular domain for ligand binding and the intracellular kinase domain for the enzymatic reaction.
236
How does ligand binding work with steroid receptors?
In the resting state, the steroid receptor is bound by a chaperone in the cytoplasm. Ligand passes through the cell membrane and into the cytoplasm, where it binds the receptor. The new ligand/receptor complex separates from the chaperone and moves into the nuclear membrane. It will then bind to the specific sequence of DNA to act as a transcription factor.
237
How does estrogen binding to its steroid receptor work?
Estrogen binds as all steroids do to steroid receptors. Estrogen and its receptor acting as a transcription factor can turn many genes off and on.
238
What are G-protein coupled receptors?
These receptors span the cell membrane. It has an outside part that ligands bind to that converts it to the ‘on’ state, where the alpha subunit releases GDP and GTP replaces it.
239
What are partial agonists?
These drugs bind and activate a receptor but only have partial efficacy at the receptor.
240
What are the dose-response curves for a full agonist, partial agonist, antagonist, and inverse agonist?
Full agonist is the full curve
Partial agonist is partial curve
Antagonist is a straight line
inverse agonist is negative curve
241
What is the volume of distribution?
This is the dose of a drug needed to achieve a given concentration. However, it is not a measurement of volume. It reflects the localization of the drug in the plasma versus tissues and free versus bound.
242
When the plasma concentration of the drug is __________, the volume of distribution will be __________. When the plasma concentration is HIGH, the volume of distribution will be LOW.
LOW; HIGH
243
Why would lower protein binding and increased membrane binding increase the volume of distribution (Vd)?
Lower protein binding means it is not floating around in circulation as much and wants to bind to its protein of activation. This allows the drug to leave circulation more readily and enter the peripheral tissues leading to a higher Vd.
244
On a basic level, what is the goal of drug metabolism?
To turn the lipophilic drugs we start with into hydrophilic drugs so the kidneys can excrete it.
245
What are the two phases of drug/prodrug metabolism?
Phase 1- small chemical groups added
Phase 2- large chemical groups added
246
What are some examples of Phase 1 metabolism enzymes and reactions?
Oxidation by P-450 enzymes, reduction, and hydrolysis.
247
What are some examples of Phase 2 metabolism enzymes and reactions?
Addition of glucoronidate, sulfates, alkylates, glutathione, and more.
248
Hydrophilic drugs are typically excreted via the kidneys. Hydrophobic drugs are excreted via the liver. When a drug is non-polar, the _______ may modify the drug to become polarized so it can excreted by the _________.
Liver: Kidneys
249
What is clearance?
The volume of plasma from which a drug is cleared in a unit of time (mL/min). Clearance is heavily dependent on a drug’s volume of distribution and half-life.
250
What is the equation for clearance?
251
If a drug had a high volume of distribution, why would it have a longer half-life?
A higher volume of distribution means it leave circulation and enters the peripheral more readily. It then needs to come back into circulation for it to be cleared. This takes time so a longer half-life is needed.
252
What are JAK kinases?
When cytokines bind to their receptor, kinase binds to the receptor inside the cell. Janus Kinases have two kinase domains. Since cytokine receptors have no activity, they rely on JAK kinases to relay their signal once cytokine is bound.
253
How is the loading dose calculated?
254
Lipophilic (fat-loving) drugs tend to cross membranes and _______ the circulation. While less lipophilic drugs tend to _________ in circulation.
Leave; stay
255
What type of proteins do acidic drugs and hydrophobic drugs typically bind to?
Albumin
256
What types of protein do basic drugs typically bind to?
Acid glycoproteins
257
What is a therapeutic index?
The is the LD50/ED50. A high therapeutic index is a safer drug.
258
If affinity decreases, Kd __________.
If affinity increases, Kd __________.
Increases: Decreases
259
What is Kd?
The unique concentration of a drug will occupy 50% of the total receptor population.
260
In the graph above, A represents maximum activity of a target protein, and B represents the same effect in the presence of an inhibitor. Based on the mechanism of the drugs listed below, which one is best represented by curve B?
A. Amoxicillin
B. Diphenhydramine
C. Methotrexate
D. Omeprazole
D. Omeprazole
261
Which of the following options is effective and practical for increasing bulk to relieve typical constipation in a child?
A. Aloe
B. Linaclotide
C. Mineraloil
D. Polyethylene glycol
D. Polyethylene Glycol
262
What is the mnemonic for common side effects of diuretics?
You give HHED (hypovolemia, hypokalemia, electrolyte imbalance, dizziness) to the D (diuretics).
263
What is the mnemonic for common side effects of ACE inhibitors?
If you want an ACE, you will need FADHH (fatigue, angioedema, dry cough, hypotension, hyperkalemia)
264
What is the mnemonic for common side effects of angiotensin receptor blockers (ARBs)?
Don't Fucking Hide Vape (DFHV: dizziness, fainting, headache, vomiting) or I will hit you with my AR (17).
265
What is the mnemonic for common side effects of beta-1 blockers?
B-1 blockers make you BIFc (bradycardia, impotence, fatigue, cold extremities)
266
What is the mnemonic for common side effects of alpha-1 blockers?
JUST 1ST DOSE SYNCOPE
267
What is the mnemonic for common side effects of calcium channel blockers?
HAA! (hypertension, angina, arrhythmia) Mckayala on a CCB has bpd (bradycardia, palpitations, dizziness)
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