drugs Flashcards

Question 1

Q

Methotrexate

Answer

A

<ul>
<li>Antimetabolite</li>
<li>AntifolateChemotherapy (Folic acid analog)</li>
<li>Cytotoxic Agent (target all dividing cells)</li>
</ul>

Question 2

Q

Mechanism of action of methotrexate: What is the primary target?

Answer

A

Dihydrofolate reductase (DHFR)

Question 3

Q

Mechanism of action of methotrexate

Answer

A

Reduces synthesis of purines

Reduces synthesis of dTMP by inhibiting the necessary cofactor for thymidylate synthetase

Reduces cellular proliferation and induces cellular death by preventing synthesis of RNA and DNA

Question 4

Q

Methotrexate therapeutic uses

Answer

A

Useful as single agent in treating acute lymphoblastic leukemia in children

Osteosarcomas often treated with high doses.
Choriocarcinoma (cancer in women’s womb that often originates from placental precursor cells)
Cure rate is 75-90 % with sequential treatments with methotrexate and dactinomycin.
Part of combination therapy for some types of lymphomas, leukemias, and cancers of the breast, head and neck, ovary, and bladder.

Question 5

Q

Methotrexate therapeutic uses

Answer

A

Useful as single agent in treating acute lymphoblastic leukemia in children

Osteosarcomas often treated with high doses.
Choriocarcinoma (cancer in women’s womb that often originates from placental precursor cells)
Cure rate is 75-90 % with sequential treatments with methotrexate and dactinomycin.
Part of combination therapy for some types of lymphomas, leukemias, and cancers of the breast, head and neck, ovary, and bladder.

Question 6

Q

How do you reduce Methotrexate toxicity?

Answer

A

<ul>
<li>Leucovorin rescue</li>
<li>Leucovorin is administered after and otherwise lethal dose of methotrexate is administered.</li>
</ul>

Question 7

Q

Methotrexate Resistance

|

Answer

A

<ul>
<li>Impaired transport</li>
<li>Altered forms of DHFR with decreased affinity for methotrexate</li>
<li>Elevated DHFR expression (gene amplification)</li>
<li>Numerous other mechanisms</li>
</ul>

Question 8

Q

Methotrexate Toxicities

|

Answer

A

Nephrotoxicity

|

Question 9

Q

5-fluorouracil (5-FU) (4 things)

|

Answer

A

<p><p><p><ul>
	<li>inhibits thymidylate synthase</li>
	<li>Pyrimidine Analog</li>
	<li>Antimetabolite</li>
	<li>Cytotoxi Agent</li>
</ul>
</p></p></p>

Question 10

Q

Mechanism of action of 5-fluorouracil (5-FU)

Answer

A

<ul>
<li>5-FU is metabolized into 5-fluorodeoxyuridine monophosphate (FdUMP), which inhibits thymidylate synthase.</li>
<li>Causes DNA damage by decreasing thymidylate (dTMP) levels, leading to cell death</li>
</ul>

Question 11

Q

Capecitabine (4 things)

|

Answer

A

<p><p><p><ul>
	<li>Antimetabolite</li>
	<li>Pyrimidine analog</li>
	<li>is a prodrug of 5-FU that had improved oral bioavailability allowing it to be given orally.</li>
	<li>Cytotoxic Agent</li>
</ul>
</p></p></p>

Question 12

Q

Resistance to 5-FU can be associated with

Answer

A

amplification of thymidylate synthetase.

|

Question 13

Q

5-FU used as a component of

Answer

A

chemotherapy regimens for breast cancer, head and neck cancers, colorectal, and gastrointestinal.

Question 14

Q

5-FU Rarely used as

Answer

A

a single agent

|

Question 15

Q

5-FU Adverse effects

Answer

A

include oral and GI ulcers and bone marrow suppression

Question 16

Q

Capecitabine (3 things)

Answer

A

Antimetabolite
Pyrimidine analog
is a prodrug of 5-FU that had improved oral bioavailability allowing it to be given orally.

Question 17

Q

Most important antimetabolite to treat acute myelogenous leukemia (AML)

Answer

A

<ul>
<li>Cytarabine (cytosine arabinoside, ara-C)</li>
<li>Only used in treatment of hematologic malignancies</li>
<li>Ara-C is an analog of cytosine.</li>
</ul>

Question 18

Q

Ara-CTP incorporation into DNA inhibits

Answer

A

DNA polymerase, thus halting elongation of DNA molecules

Question 19

Q

Cytarabine (cytosine arabinoside, ara-C) Only active in

Answer

A

S-Phase

Question 20

Q

Cytidine deaminase inactivates

Answer

A

ara-C.

|

Question 21

Q

Cytarabine clinical toxicities

|

Answer

A

<ul>
<li>Cytidine deaminase levels are quite low in the central nervous system. CNS exposed to higher concentrations than the rest of the body.
<ul>
<li>Can cause cerebellar syndrome Dysarthria (motor speech disorder)</li>
</ul>
</li>
<li>Toxicity is strongly correlated with renal dysfunction, hepatic dysfunction, and advancing age. 
</li>
</ul>

Question 22

Q

Gemcitabine resistance

|

Answer

A

Reduced activity of deoxycytidine kinase
Tumors increasing production of deoxycytidine

Question 23

Q

Cytarabine (3)

|

Answer

A

<p><p><p><ul>
	<li>Antimetabolite</li>
	<li>Pyrimidine analog</li>
	<li>Cytotoxic Agent</li>
</ul>
</p></p></p>

Question 24

Q

Gemcitabine(3)

Answer

A

<p></p><p></p><p></p><ul>
	<li>Antimetabolite</li>
	<li>Pyrimidine analog</li>
	<li>Cytotoxic agent</li>
</ul>

Question 25

Q

Gemcitabine Cytotoxic effects

Answer

A

<ul>
<li>Incorporated into DNA, which inhibits synthesis and function</li>
<li>Inhibits ribonucleotide reductase (reduces pools of dNTPs, which are necessary for DNA synthesis</li>
</ul>

Question 26

Q

Gemcitabine used in treatment of

Answer

A

a wide range of cancers including: pancreatic, non–small cell lung, ovarian, bladder, etc…

Question 27

Q

Gemcitabine resistance

|

Answer

A

Reduced activity of deoxycytidine kinase Tumors increasing production of deoxycytidine

Question 28

Q

6-Thioguanine (6-TG) (4)

Answer

A

<p></p><p></p><ul>
	<li>Cytotoxic agent</li>
	<li>Antimetabolite</li>
	<li>Purine analog</li>
	<li>treatment of acute lymphoblastic leukemis.</li>
</ul>

Question 29

Q

6-Mercaptopurine (6-MP) (4)

Answer

A

<p></p><p></p><ul>
	<li>Cytotoxic agent</li>
	<li>antimetabolite</li>
	<li>Purine analog</li>
	<li>Treatment of acute lymphoblastic leukemia</li>
</ul>

Question 30

Q

6-Thioguanine (6-TG) 6-Mercaptopurine (6-MP)

Answer

A

<ul>
<li>6-MP was the first purine analog used in cancer chemotherapy</li>
<li>Treatment of acute lymphoblastic leukemia (ALL)</li>
<li>Largely replaced by newer antipurines fludarabine and cladribine</li>
</ul>

Question 31

Q

Mechanism of action of 6-TG (6-Thioguanine)

Answer

A

<ul>
<li>activated to thio-GMP and thio-IMP hypoxanthine-guanine phospho- ribosyl transferase (HGPRT).</li>
<li>Decreased activity of HGPRT common mechanism of resistance.</li>
<li>Thiopurine methyltransferase (TPMT) inactivates 6-MP.</li>
<li>Common gene variant (polymorphism) causes reduced TPMT activity.
<ul>
<li>Can lead to life-threatening toxicity</li>
</ul>
</li>
</ul>

Question 32

Q

Mechanism of action of 6-Mercaptopurine (6-MP)

Answer

A

<ul>
<li>activated to thio-GMP and thio-IMP hypoxanthine-guanine phospho- ribosyl transferase (HGPRT).</li>
<li>Decreased activity of HGPRT common mechanism of resistance.</li>
<li>Thiopurine methyltransferase (TPMT) inactivates 6-MP.</li>
<li>Common gene variant (polymorphism) causes reduced TPMT activity.
<ul>
<li>Can lead to life-threatening toxicity</li>
</ul>
</li>
</ul>

Question 33

Q

Fludarabine (4)

Answer

A

<p></p><p></p><ul>
	<li>Cytotoxic agent</li>
	<li>antimetabolite</li>
	<li>newer purine analog</li>
	<li>Commonly used to treat chronic lymphocytic leukemia (CLL) by itself or in combination with cyclophosphamide and rituximab.</li>
</ul>

Question 34

Q

Fludarabine Mechanism

Answer

A

<ul>
<li>Deoxycytidine kinase activates drug in cells by converting it to the tri-phosphate form.</li>
<li>Incorporated into DNA and RNA</li>
<li>Inhibits DNA polymerase and ribonucleotide reductase (RNR)</li>
<li>Inhibits RNA function, including mRNA translation into proteins</li>
</ul>

Question 35

Q

Fludarabine resistance

Answer

A

commonly caused be decreased activity of deoxycytidine kinase and drug efflux.

Question 36

Q

Cladribine (4)

Answer

A

<p></p><p></p><ul>
	<li>Cytotoxic Agent</li>
	<li>Newer purine analog</li>
	<li>antimetabolite</li>
	<li>Standard therapy for hairy cell leukemia (HCL) (curative intent) "when your HAIR gets wet it DRIPS"--> claDRIBine</li>
</ul>

Question 37

Q

Cladribine Mechanism

Answer

A

<ul>
<li>Deoxycytidine kinase activates drug in cells by converting it to the tri-phosphate form.</li>
<li>Incorporated into DNA</li>
<li>Causes strand breaks</li>
<li>Potent inhibitor of ribonucleotide reductase (RNR)</li>
</ul>

Question 38

Q

Cladribine resistance

Answer

A

commonly is associated with decreased activity of deoxycytidine kinase, drug efflux, and increased RNR expression

Question 39

Q

Methotrexate Mechanism

|

Answer

A

Inhibits dihydrofolate reductase, which reduces precursors for RNA and DNA synthesis

Question 40

Q

5-fluorouracil (5-FU)

| Mechanism

Answer

A

Incorporated into DNA and RNA, which inhibits synthesis and function
Inhibits thymidylate synthetase, which reduces DNA precursors

Question 41

Q

Cytarabine (ara-C)

| mechanism

Answer

A

Incorporated into DNA and RNA, which inhibits synthesis and function
Inhibits DNA synthesis by inhibiting DNA polymerase

Question 42

Q

Gemcitabine Mechanism

Answer

A

Incorporated into DNA, which inhibits synthesis and function
Inhibits ribonucleotide reductase (RNR), which reduces precursors for DNA

Question 43

Q

6-MP and 6-TG

| Mechanism

Answer

A

Incorporated into DNA, which inhibits synthesis and function
Reduce precursors for RNA and DNA by inhibiting purine synthesis

Question 44

Q

Cladribine

| Mechanism

Answer

A

Incorporated into DNA
Causes strand breaks
Potent inhibitor of ribonucleotide reductase (RNR), which reduces DNA precursors

Question 45

Q

Cladribine

| Mechanism

Answer

A

Incorporated into DNA
Causes strand breaks
Potent inhibitor of ribonucleotide reductase (RNR), which reduces DNA precursors

Question 46

Q

General mechanisms of alkylating agents

Answer

A

<ul>
<li>Among the oldest and most useful class</li>
<li>Reactions between alkyl groups on drug with nucleophilic groups on proteins and nucleic acids</li>
<li>Most common binding site is seven-nitrogen group of guanine</li>
<li>Cause DNA crosslinking and strand breakage</li>
</ul>

Question 47

Q

Alkylating agents

Answer

A

Cytotoxic cell cycle nonspecific agents (they are toxic in all stages of cell cycle)

Question 48

Q

Common alkylating agents

|

Answer

A

<ul>
<li>Nitrogen mustards
<ul>
<li>Related to the ‘mustard gas’ used during the First World War</li>
<li>Examples include: Mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide</li>
</ul>
</li>
<li>Nitrosoureas
<ul>
<li>Carmustine (BCNU) and lomustine</li>
</ul>
</li>
</ul>

Question 49

Q

Cyclophosphamide (4)

Answer

A

<ul>
<li>Cytotoxic Agent</li>
<li>Alkylating agent</li>
<li>Nitrogen Mustard</li>
<li>most commonly used alkylating agent in both solid tumors and hematological malignancies.</li>
<li>Hemorrhagic cystitis caused by acrolein (5-10% of patients)</li>
</ul>

Question 50

Q

mesna

Answer

A

<ul>
<li>Co-administration of mesna (with cyclophosphamide), a sulfhydryl compound, inactivates acrolein (cytotoxic to bladder cells).</li>
<li>Reduces risk of hemorrhagic cystitis</li>
</ul>

Question 51

Q

Resistance to alkylating agents

Answer

A

Inactivation by glutathione and other nucleophiles (increased glutathione production)
Reduced uptake
Accelerated DNA repair
Increased expression of O6-methylguanine-DNA methyltransferase (MGMT)
MGMT prevents permanent DNA damage by removing alkyl groups from guanine before cross-links form

Question 52

Q

Resistance to alkylating agents

|

Answer

A

<ul>
<li>Inactivation by glutathione and other nucleophiles (increased glutathione production)</li>
<li>Reduced uptake</li>
<li>Accelerated DNA repair</li>
<li>Increased expression of O6-methylguanine-DNA methyltransferase (MGMT)
<ul>
<li>MGMT prevents permanent DNA damage by removing alkyl groups from guanine before cross-links form</li>
</ul>
</li>
</ul>

Question 53

Q

Non-classical alkylating agents

Answer

A

(Platinum compounds)
Considered non-classical alkylating agents because while they lead to DNA cross-linkages, they have no alkyl group like the classical alkylating agents.
Targets nucleophilic center (primarily at guanine-N7
Actively transported into cells via a Cu2+ transporter

Question 54

Q

Cisplatin

Answer

A

<p>1st generation platinum agent
cytotixic agent
non-classical alkylating agent
platinum analog
</p>

Question 55

Q

Carboplatin

Answer

A

<p>2nd generation platinum agent
cytotixic agent
non-classical alkylating agent
platinum analog
</p>

Question 56

Q

Oxaliplatin

Answer

A

3rd generation platinum agent
cytotixic agent
non-classical alkylating agent
platinum analog

Question 57

Q

Non-classical alkylating agents

| Commonly used to

Answer

A

ovarian, testicular, head and neck, bladder, esophagus, lung, and colon cancers

Question 58

Q

Cisplatin

| adverse effects

Answer

A

Anaphylactic-like reactions (hypersensitivity reactions)
Peripheral motor and sensory neuropathy
Nephrotoxicity
Can be significantly reduced by increasing hydration by co-administering intravenous saline

Question 59

Q

Cisplatin

| adverse effects

Answer

A

Anaphylactic-like reactions (hypersensitivity reactions)
Peripheral motor and sensory neuropathy
Nephrotoxicity
Can be significantly reduced by increasing hydration by co-administering intravenous saline

Question 60

Q

Vinblastine

Answer

A

<ul>
<li>Cytotoxic agent</li>
<li>Plant dericatives and similar compounds</li>
<li>vinca alkaloid (from periwinkle plant)</li>
<li>Antimicrotubule agents</li>
</ul>

Question 61

Q

Vincristine

Answer

A

<ul>
<li>Cytotoxic agent</li>
<li>Plant dericatives and similar compounds</li>
<li>vinca alkaloid (from periwinkle plant)</li>
<li>Antimicrotubule agents</li>
</ul>

Question 62

Q

Adverse effects of vincristine

|

Answer

A

Mostly neurological (numbness and tingling in extremities, motor weakness)

Question 63

Q

Paclitaxel (taxol)

Answer

A

<ul>
	<li>Cytotoxic agent</li>
	<li>Plant derivatives and similar compounds</li>
	<li>Taxanes</li>
	<li>Antimicrotubule agents</li>
</ul>

Question 64

Q

Paclitaxel (taxol) mechanism

Answer

A

Paclitaxel kills tumor cells by arresting them in mitosis by preventing the depolymerization of microtubules.

Answer 65

A

peripheral neuropathy

|

Answer 66

A

<ul>
<li>(granulocyte-colony stimulating factor) used often with Paclitaxel to reduce myelosuppression</li>
<li>Hypersensitivity allergic reactions occur in about 5 % of the patients receiving paclitaxel.
<ul>
<li>This is largely prevented when patients are pretreated with dexamethasone and anti-histamines.</li>
</ul>
</li>
</ul>

Answer 67

A

<ul>
<li>cytotoxic agent</li>
<li>plant derivative and similar compound</li>
<li>camptothecins analog</li>
<li>induce cytotoxicity by inhibiting topoisomerase I (prevents repair of cuts leading to DNA damage).</li>
</ul>

Answer 68

A

cytotoxic agent
plant derivative and similar compound
other

is a class II topoisomerase inhibitor

Answer 69

A

<ul>
<li>cytotoxic agent</li>
<li>plant derivative and similar compound</li>
<li>other</li>
<li>is a class II topoisomerase inhibitor</li>
</ul>

Answer 70

A

cytotoxic antibiotics

anthracyclines (anthracycline antibiotic)

Answer 71

A

It intercalates with DNA, leading to the inhibition DNA polymerase.

Inhibits topoisomerase II
Cause DNA double-strand breaks, which can lead to cell death

Doxorubicin binds to iron and generates free radicals, which lead to DNA and protein damage.

Free radical formation causes adverse effects, but not thought to be the major mechanism of tumor cell killing,

Answer 72

A

Irreversible cardiomyopathy

Answer 73

A

Cytotoxic Anitibiotics

Answer 74

A

Small peptide that binds to DNA and causes single and double strand breaks

Cell cycle specific drug (causes cells to arrest in G2 phase)

Importantly, bleomycin is minimally myelosuppressive and immunosuppressive (used in combination therapy with other cytotoxic drugs)

Answer 75

A

curative combination chemotherapy regimens for testicular cancer and Hodgkin’s disease

Answer 76

A

Dose-limiting adverse side effect is pulmonary toxicity

Effects are cumulative and irreversible

Answer 77

A

myelosuppression

Answer 78

A

hormone
glucocorticoid
Inhibit lymphocyte proliferation
Used to treat leukemias and lymphomas
Useful in reducing intracranial pressure associated with brain tumors
Useful to reduce adverse effects of chemotherapeutics such as nausea and vomiting

Answer 79

A

hormone
glucocorticoid
Inhibit lymphocyte proliferation
Used to treat leukemias and lymphomas
Useful in reducing intracranial pressure associated with brain tumors
Useful to reduce adverse effects of chemotherapeutics such as nausea and vomiting

Answer 80

A

Partial estrogen receptor antagonist
Selective estrogen receptor modulator (SERM)
Tamoxifen is a non-steroidal that competitively binds to estrogen receptor and reduces the growth of estrogen dependent breast cancers

Answer 81

A

Androgen receptor antagonists that are useful for the treatment of prostate cancer
These drugs prevent dihydrotestosterone from binding to androgen receptors

Answer 82

A

Aromatase inhibitor
Post-menopausal women synthesize estrogen from peripheral tissue where aromatase converts testosterone into estrogen.

Anastrozole inhibits aromatase activity, which can lower estrogen levels.

Answer 83

A

estrogen-sensitive (estrogen receptor-positive) breast tumors in post-menopausal women

Answer 84

A

monoclonal antibodies
HER-2 Inhibitor
Used to treat breast cancer with HER-2 amplified
First monoclonal antibody approved for the treatment of solid tumors

Answer 85

A

Most serious is cardiotoxicity

Answer 86

A

Most serious is cardiotoxicity

Answer 87

A

Targeted agent
Monoclonal antibody that binds to EGFR and blocks signaling

Used to treat EGFR-expressing colorectal tumors in combination with other drugs
Also used in combination with radiation therapy in head and neck cancers
Activating mutations in RAS in colorectal tumors cause cells to be resistant

Routine tests of RAS mutational status are performed

Answer 88

A

Bevacizumab is an monoclonal antibody directed against vascular endothelial growth factor (VEGF).

Answer 89

A

binds to VEGF, which prevents VEGF from binding to VEGFR (prevents angiogenesis).

Answer 90

A

Colorectal cancer in combination with capecitabine and oxaliplatin
It is also used in combinations with other drugs to treat metastatic breast and colorectal cancer.

Answer 91

A

Small Molecule tyrosine kinase inhibitor

Answer 92

A

Small molecule that inhibits both EGFR and HER-2 kinase activity

Answer 93

A

with capecitabine to treat HER2-amplified, trastuzumab-refractory breast cancer

Answer 94

A

Small molecule turosine kinase inhibitor
Oral small-molecule EGFR inhibitor

ATP competitive inhibitor

Answer 95

A

metastatic nonsmall cell lung carcinoma (NSCLC) in patients with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
Need to determine mutation status with and FDA approved test

Resistance often occurs due to acquired secondary mutation in EGFR or by amplification of the MET oncogene.

Answer 96

A

Small molecule tyrosine kinase inhibitor
Imatinib (Gleevec) is a small molecular inhibitor of BCR-ABL

Imatinib (and related compounds) induces remission (both clinical and molecular) in greater than 90 % of patients in the chronic phase of the disease.

Answer 97

A

the Philadelphia chromosome translocation.

Fusion protein between BCR and the ABL tyrosine kinase

Leads to constitutive activation of ABL

Answer 98

A

Point mutations in BCR-ABL cause a reduced affinity for imatinib

Fortunately, the analogs of imatinib (nilotinib and dasatinib) can still inhibit BCR-ABL with many of these mutations

Answer 99

A

Miscellaneous
Enzyme used to treat childhood acute lymphoblastic leukemia (ALL)

Hydrolyzes plasma L-asparagine into L-aspartate

While normal cells can synthesize sufficient L-asparagine, tumor cells cannot.

Thus, asparaginase can starve tumor cells of L-asparagine.

Answer 100

A

allergic hypersensitivity reaction (fever, chills, rash, hives)
Can become severe causing respiratory failure and hypotension

Answer 101

A

(proteasome inhibitor)

Answer 102

A

By inhibiting the proteasome, it elevates levels of p53

Can also reduce levels of a protein that normally inhibits apoptosis called NF-kappaB

Answer 103

A

patients with relapsed or refractory multiple myeloma

Answer 104

A

Peripheral neuropathy is most the most chronic toxicity

Answer 105

A

Used to treat renal cell carcinoma
Inhibition of mTOR complex 1 (mTORC1) reduces protein translation, promotes cell cycle inhibition, and promotes apoptosis.

Answer 106

A

mTOR forms a complex called mTOR complex 2 (mTORC2)

mTORC2 is not inhibited by temsirolimus

Answer 107

A

cisplatin, methotrexate

Answer 108

A

vincristine, cytarabine (ara C), cisplatin, bortezomib, paclitaxel

Answer 109

A

doxorubicin,

trastuzumab

Answer 110

A

methotrexate, bleomycin,
alkylating
agents

Answer 111

A

cyclophosphamide

Answer 112

A

asparaginase,

paclitaxel

Answer 113

A

Cytotoxic agent
alkylating agent
nitrogen mustards
Related to the ‘mustard gas’ used during the First World War

“Cytotoxic cell cycle nonspecific agents (they are toxic in all stages of cell cycle)
“

Answer 114

A

Considered non-classical alkylating agents because while they lead to DNA cross-linkages, they have no alkyl group like the classical alkylating agents.
Targets nucleophilic center (primarily at guanine-N7

(3rd generation)
Actively transported into cells via a Cu2+ transporter
Commonly used to ovarian, testicular, head and neck, bladder, esophagus, lung, and colon cancers

Answer 115

A

Iron chelator

used with Doxorubicin to reduce cardiotoxicity

Answer 116

A

Aspirin irreversibly blocks cyclooxygenase -1 (COX-1) in platelets.

Reduces thromboxane A2 production (which leads to reduced platelets activation and aggregation).

Other agents that inhibit COX-1 reversibly do not have antiplatelet effects (e.g., ibuprofen).

Answer 117

A

Elevated cAMP levels reduce intracellular Ca2+ levels (reduce activation of platelets).
Dipyridamole is a vasodilator that can be used in combination with warfarin to inhibit embolization from mechanical heart valves.
By itself, dipyridamole has little anti-thrombotic effects.

Answer 118

A

irreversible P2Y12 inhibitors that are prodrugs that have to be activated by metabolism in the liver

has to be activated by CYP2C19

Answer 119

A

irreversible P2Y12 inhibitors that are prodrugs that have to be activated by metabolism in the liver

Answer 120

A

P2Y12 inhibitors

do not need to be metabolized to become activated.

Is reversible

More rapid coagulation recovery upon discontinuation

Answer 121

A

P2Y12 inhibitors

do not need to be metabolized to become activated.

Is reversible

More rapid coagulation recovery upon discontinuation

Answer 122

A

typically used as adjunct therapy in patients undergoing PCI to prevent ischemic complications.

Sometimes combined with heparin and aspirin as adjunct to PCI

Answer 123

A

typically used as adjunct therapy in patients undergoing PCI to prevent ischemic complications.

Sometimes combined with heparin and aspirin as adjunct to PCI

Answer 124

A

used in patients with unstable angina.

Answer 125

A

Fragment of antigen-binding (Fab) segment of a monoclonal antibody directed against GPIIb/IIIa

The binding of abciximab to GPIIb/IIa prevents platelet aggregation by preventing the fibrinogen cross-bridges from forming between platelets.

Abciximab also binds to receptors related to GPIIb/IIIa on leukocytes, which might account for the added antiinflammatory and antiproliferative effects of abciximab

Answer 126

A

a peptide that binds to and inhibits GPIIb/IIIa.

Answer 127

A

a nonpeptidic small molecule that binds to and inhibits GPIIb/IIIa.

Answer 128

A

eptifibatide and tirofiban

Answer 129

A

Protease activated receptor (PAR) antagonist

Recently approved by FDA for the prevention of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease

Answer 130

A

Heparin (parenteral)
Enoxaparin (low molecular weight heparin) (parenteral) *
Fondaparinux (parenteral) *

Answer 131

A

Lepirudin (parenteral)
Bivalirudin (parenteral)
Argatroban (parenteral)
Dabigatran (oral)**

Answer 132

A

Rivaroxaban (oral) **

Apixaban (oral) **

Answer 133

A

Warfarin (oral)

Answer 134

A

is a proteoglycan found on the surface of vascular endothelial cells.
Binds to antithrombin to increase inhibition of factor Xa and thrombin

Answer 135

A

A specific pentasaccharide sequence in heparin binds to antithrombin (AT)
Changes conformation of AT causing it to have a higher affinity for factor Xa
This accelerates the rate of factor Xa inhibition without affecting thrombin inhibition.
Heparin can also increase AT-induced inhibition of thrombin.
It does this by acting as a molecular bridge that brings thrombin into close contact with AT.
Only longer heparin molecules can facilitate this .

Answer 136

A

sulfated-polysaccharides of varying molecular weights found in mast cells and thought to be required for histamine storage.
Not normally found in the plasma

Answer 137

A

tissues rich in mast cells (usually animal intestines or lungs)

Answer 138

A

parenterally to inhibit coagulation

Answer 139

A

Heparin has to be administered parenterally.

To achieve anticoagulant effect rapidly, heparin is usually administered intravenously.

Answer 140

A

Binds not only to antithrombin, but other plasma proteins, and endothelium of vessel walls

Interaction with plasma proteins other than antithrombin reduces anticoagulant activity
Acute-phase proteins (plasma proteins that change in response to inflammation), which can be elevated in ill patients
Platelet factor 4 (PF4) (secreted by platelets)

Levels of heparin binding proteins differ from person to person cause fixed doses to be unpredictable.

Answer 141

A

Non-saturable involving the kidneys and liver

A rapid process of binding to and being taken up by endothelial cells

Because binding sites on endothelial cells are limited, this is a saturable process (as the dose of heparin increases there are fewer sites to bind).

Thus, clearance decreases as dose increases (dose-dependent clearance).

Remember, t1/2 = 0.693 x Vd/CL.

Thus, t1/2 increases as dose increase.

Does of 100, 400, 800 units/kg (half lives of anticoagulant activity are approx. 1, 2.5, and 5 hours, respectively).

Answer 142

A

Activated partial thromboplastin time (aPTT)

Also called partial thromboplastin time (PTT)

Place patient’s anticoagulated (citrate), platelet poor plasma in tube and mixed with phospholipids, and a negatively charged surface like glass beads, which initiates the intrinsic pathway.

Ca2+ addition initiates clotting reaction and the time it takes the blood to clot is measured.

Answer 143

A

Most common complication is bleeding
Bleeding can occur in patients within normal therapeutic range.
Because heparin has short ½ life, discontinuation of administration often used to stop mild bleeding.
If bleeding is severe, protamine sulfate can be administered to inhibit heparin.
Protamine is a basic polypeptides that binds to and inactivate longer heparin molecules.

Osteoporosis
Long term heparin usage (> 1-6 months)

Answer 144

A

Uncommon

Significant mortality

Immune thrombocytopenia

Heparin can bind platelet-secreted platelet factor 4.

Antibodies are generated towards PF4/heparin complex.

Antibodies can bind to platelets and activate them and cause them to be cleared by macrophages.

Causes venous and arterial thrombosis

Answer 145

A

Low molecular weight heparin (LMWH)
Administered  parenterally (subcutaneously once or twice per day)

Prepared from unfractionated heparin by depolymerization

Advantages over heparin and has replaced heparin for some indications

LMWH is not long enough to facilitate binding of thrombin to AT.
Thus, it primarily acts as an indirect inhibitor of factor Xa.

Answer 146

A

by kidney

Thus, LMWH is contraindicated for use in patients with severe renal insufficiency.

Answer 147

A

Synthetic analog of the AT-binding pentasacharide sequence

Alternative to heparin or LMWH for initial treatment of established venous thromboembolism

Only inhibits factor Xa because to short to affect thrombin binding

Protamine does not reverse (cannot be used as an antidote)

Answer 148

A

by kidney

Fondaparinux is contraindicated in patients with severe renal insufficiency

Answer 149

A

recombinant from of hirudin.(a compound isolated from the leach, was the first DTI to be used.)

Answer 150

A

bind at both the fibrin binding site and the active site of thrombin (bivalent).

Answer 151

A

are small molecular inhibitors that bind only to active site of thrombin (univalent).

Answer 152

A

Parenteral:

Answer 153

A

Both heparin/antithrombin complex and DTIs can inhibit soluble thrombin.
However, only the DTIs can inhibit thrombin bound to fibrin.
Heparin binds both fibrin and thrombin independently of heparin/AT complex.
This prevents heparin/AT complex from binding to thrombin

Answer 154

A

DTIs do not cause heparin-induced thrombocytopenia.
The main drawback of DTIs is that specific antidotes do not exist, or are not as well established.
There is a humanized dabigatran-specific (Fab) antibody fragments under development as dabigatran antidote.
Hemodialysis and administration of active factor VII or prothrombin complex concentrate can be used to reverse bleeding

Answer 155

A

Prevent progression or recurrence of venous thrombosis and thromboembolism (DVT, atrial fibrillation, mechanical heart valves, major surgeries)

Also given to patients with acute myocardial infarction to prevent recurrent coronary ischemia

Useful in long-term management because it is orally active

Answer 156

A

vitamin K.

Warfarin competes with vitamin K for vitamin K reductase (VCORC1).

Answer 157

A

Activity of Factors II, VII, IX, and X are vitamin K dependent

Activity of protein C and protein S are also vitamin K dependent

A reduced form of vitamin K is used as a cofactor in the carboxylation of key glutamate residues in these factors.

Allows Ca2+ to bind, which facilitates activation of these factors

Answer 158

A

anticoagulant that works by inhibiting vitamin K reduction leading to a decrease in activation of Factors II, VII , IX and X.

Answer 159

A

Close to 100 % oral bioavailability
Highly bound to serum albumin (only unbound drug is active)
Small volume of distribution
Full antithrombotic effect takes about 3-5 days
Warfarin does not reduce activity of previously synthesized coagulation factors (½ life of prothrombin is approx. 48 hours).
Thus, at onset of warfarin treatment some patients are supplemented with fast acting anticoagulants (heparin, LMWH, or fondaparinux).
Long therapeutic ½ life (time to normal coagulation after cessation approx. 5-7 days)

Answer 160

A

Difficult to predict severity and clinical significance of many of them

However, the following drugs appear to have a high probability of causing clinically significant potentiation or inhibition of the anticoagulant effect of warfarin

Drugs that potentiate warfarin’s effect increase INR
Drugs that inhibit warfarin’s effect decrease INR

Answer 161

A

Decreased hepatic function with liver disease can decrease the clearance of warfarin (increase INR)

Diseases of the intestine (such as Crohn’s disease) that reduce vitamin K absorption (increase INR)

Renal insufficiency can cause hypoalbuminemia (increase INR)
Remember that warfarin binds highly to plasma albumin and that warfarin bound to albumin is inactive.
Less albumin means more free (active) warfarin
Drugs like aspirin that bind highly to albumin can compete with warfarin for binding to albumin (increase in INR).

Answer 162

A

Hemorrhage (most common)
Placental transfer 
Birth defects
Necrosis (rare disorder)
Believed to be caused by a precipitous fall in protein C

Leads to a hypercoagulable state

Patients with low protein C levels for genetic reasons might be more susceptible.

Answer 163

A

No real antagonists

If reversal of warfarin anticoagulant effect is necessary, vitamin K can be administered.

Reversal requires time because new factors have to be synthesized

Emergent reversal can be accomplished by administering fresh plasma.

Answer 164

A

Xa inhibitor
New oral anticoagulants
Oral direct Factor Xa inhibitor

Used for thromboprophylaxis after hip or knee replacement surgery, DVT, pulmonary embolism, atrial fibrillation
Standard therapy for pulmonary embolism is heparin overlapped with and following by vitamin K antagonist (warfarin)
Research shows that rivaroxaban is as efficacious as standard therapy, but there are significantly less major bleeding events with rivaroxaban.

Answer 165

A

New oral anticoagulants

Xa inhibitor

Answer 166

A

thrombin inhibitor
New oral anticoagulants

Oral thrombin inhibitor

Administered for stroke prevention in atrial fibrillation and treatment and prevention of DVT and pulmonary embolism

Dabigatran reported to be as effective as warfarin in preventing stroke and systemic embolism in patients with atrial fibrillation

Lower rates of major hemorrhage (N Engl J Med 2009; 361:1139-1151 September 17, 2009)

As effective as warfarin for extended use in treatment of thromboembolism with less bleeding (N Engl J Med 2013 Feb 21;368(8):709-18)

Contraindicated in patients with mechanical heart valves (warfarin should be used instead)

Answer 167

A

agents have benefits over warfarin
Faster onset of action
Larger therapeutic window
Low potential for food and drug interactions
Predictable anticoagulant effect removing need for routine monitoring
While overall bleeding risk is similar to warfarin, there is a lower risk of intracranial/intracerebral bleeding than warfarin.

Answer 168

A

recombinant human t-PA

Answer 169

A

The main drugs are tissue plasminogen activators (tPAs), for example alteplase.
The main use is in acute myocardial infarction, with ST segment elevation on the ECG within 12h of onset (the earlier the better!).

Other uses include:
Acute thrombotic stroke within 3h of onset (tPA), in selected patients
Clearing thrombosed shunts and cannulae
Acute arterial thromboembolism
Life-threatening deep vein thrombosis and pulmonary embolism (streptokinase, given promptly)

Answer 170

A

used in patients with unstable angina.

Answer 171

A

Block fast inward Na+ channels to varying degrees in conductive tissues of the heart
Prolong ERP  ERP/APD increased
useful in varying degrees for ventricular dysrhythmia and/or digitalis or MI-induced arrhythmia

Answer 172

A

‘Moderate’ binding to Na+ channels-moderate effects on phase 0 depolarization
K+ channel blockade-delayed phase 3 repolarization-prolonged QRS and QT
Ca2+ channel blocking effect at high doses-depressed phase 2 and nodal phase 0

Answer 173

A

Quinidine, Procainamide, Disopyramide

Answer 174

A

Primary: Block rapid inward Na+ channel

Multiple actions – dose-dependent effects
Block K+ channels - increase APD
Block α receptors - decrease BP
Block M receptors - increaseHR in intact subjects

Answer 175

A

refractory patients to
Convert symptomatic AF or flutter
Prevent recurrences of AF
Treat documented, life-threatening ventricular arrhythmias

Answer 176

A

nausea, vomiting, diarrhea (most common)
cinchonism (tinnitus, hearing loss, blurred vision)
hypotension due to α-adrenergic blocking effect
proarrhythmic (torsades de pointes – increased QT interval)

Answer 177

A

Block rapid inward Na+ channel–>slows
conduction, automaticity, excitability
in
Atrial myocardium, Ventricular myocardium, Purkinje fibers

Blocks K+ channels–> prolongs APD & refractoriness

Cf. Quinidine: Procainamide has very little vagolytic activity and does not prolong the QT interval to as great an extent

Answer 178

A

Ventricular:
treat documented, life-threatening ventricular arrhythmias
suppress ventricular arrhythmias that occur immediately following MI or to convert sustained VT (IV loading takes 20 min–> use limited to situations when adequate time is available).

Supraventricular: acute treatment of
Reentrant SVT
Atrial fibrillation
Atrial flutter associated with Wolff-Parkinson-White syndrome

Answer 179

A

arrhythmia aggravation, torsades de pointes (contraindicated in long QT syndrome, history of TdP, hypokalemia)
heart block, sinus node dysfunction

Extracardiac:
SLE-like syndrome: (15-20%, in slow acetylators) arthralgia, pericarditis, fever, weakness, skin lesions, lymphadenopathy, anemia and hepatomegaly
GI nausea and vomiting: very common
Decrease kidney functions

Answer 180

A

‘Weak’ binding to Na+ channels
weak effect on phase 0 depolarization due to rapid ‘on-off’ receptor kinetics
Accelerated phase 3 repolarization
shortened APD and QT
good use in digitalis and MI-induced arrhythmia

Answer 181

A

Lidocaine, Phenytoin, Mexiletine, Tocainide

Answer 182

A

Blocks open and inactivated Na+ channels - reduces Vmax

Shorten cardiac action potential

More effective in ischemic tissues

Lowers the slope of phase 4; altering threshold for excitability

produces variable effects in abnormal conduction system
Slows ventricular rate
Potentiates infranodal block

Answer 183

A

Used to be first-line rx for ventricular arrhythmias (post-MI)
Now (ECC/AHA 2005): second choice behind amiodarone for
immediately life-threatening or symptomatic arrhythmias
Ineffective for prophylaxis of arrhythmias after MI
Ineffective in atrial tissue

Answer 184

A

Extensive first-pass hepatic metabolism  IV use.

need multiple loading doses and a maintenance infusion

Answer 185

A

Strongest binding to Na+ channels
slow ‘on-off’ kinetics – strong effects on phase 0 depolarization
lengthened QRS and APD
Little effect on repolarization - QT unchanged
lengthened PR (depressed AV nodal conduction)

Answer 186

A

Moricizine, Flecainide, Propafenone

Answer 187

A

Strong inhibitor of Na+ channel

Can inhibits b-adrenergic R: marked structural similarity to propranolol

Answer 188

A

used primarily to treat atrial arrhythmias, PSVT, and ventricular arrhythmias in patients with no or minimal heart disease and preserved ventricular function

Answer 189

A

potent Na+ channel blockade –>prolongs phase 0 and widens QRS
markedly slows intraventricular conduction

Answer 190

A

use only in the treatment of refractory life-threatening ectopic ventricular arrhythmia
not considered a first-line agent due to propensity for fatal proarrhythmic effects

Answer 191

A

Decrease: SA nodal automaticity (phase 4)
AV nodal conduction
Ventricular contractility

Effective for supraventricular arrhythmias due to excessive sympathetic activity
Not very effective in severe arrhythmias such as recurrent VT
Are the only antiarrhythmic drugs found to be clearly effective in preventing sudden cardiac death in patients with prior MI

Answer 192

A

Multiple effects at K+, Ca2+, Na+ channels & β-receptors
Main effect: prolong phase 3 repolarization; increase QT
Useful for ventricular re-entry/fibrillatory arrhythmia
Effective in many types of arrhythmias

Answer 193

A

Dronedarone, Amiodarone, Sotalol, Ibutilide, Dofetilide - DASID

Answer 194

A

diverse pharmacologic actions

Blocks K+ channels –> prolongs refractoriness and APD
Blocks Na+ channels that are in the inactivated state
Block Ca2+ channels –> slows SA node phase 4
Slows conduction through the AV node
Noncompetitive blockade of a-, b-, and M receptors

–>Explains diverse antiarrhythmic actions

Answer 195

A

*Effective in a wide range of arrhythmias, now very widely used

Conversion and slowing of AF, maintaining sinus rhythm in AF
AV nodal reentrant tachycardia
Tachycardias associated with the WPW syndrome
PO for recurrent life-threatening VT or VF resistant to other rx
*IV for acute termination of VT or VF and is replacing lidocaineas first-line therapy for out-of-hospital cardiac arrest *

Answer 196

A

highly lipid-soluble compound
extremely variable and complex pharmacokinetics
extensively metabolized to desethyl amiodarone (DEA)
*DEA has antiarrhythmic potency (greater than or equal to) amiodarone *
rapidly concentrated in some tissues, including myocardium, but it accumulates more slowly in others –> very large VD
* Until all tissues are saturated, rapid redistribution out of the myocardium may be responsible for early recurrence of arrhythmias after discontinuation or rapid dose reduction *
After IV administration: T1/2 ~ 5 – 68 hrs
As tissues become saturated: T1/2 ~ 13 to 103 days

Answer 197

A

*IV > 5mg/kg decreases cardiac contractility & PVR –> hypotension *
likely due to polysorbate 80 or benzyl alcohol in IV formulation
Usual dosages improve myocardial contractility
* Most serious: lethal interstitial pneumonitis *, more frequent in patients with preexisting lung disease. Reversible –> CXR/3 months
* Hyperthyroidism or hypothyroidism * : diverse effects on the thyroid
Accumulation of corneal microdeposits
Photosensitivity
Elevated serum hepatic enzyme levels

Answer 198

A

*Ca2+ channel antagonists (cardiac) *
similar in utility to Class II agents with primary effects on nodal phase 0 depolarization
* depressed * SA nodal automaticity, * AV nodal conduction, decreased ventricular contractility *

Answer 199

A

Verapamil, Diltiazem

Answer 200

A

Ca2+ channel blockers (CCBs) interfere with the entry of Ca2+into cells through voltage-dependent *L- and T-type * Ca2+ channels.

The major cardiovascular sites of action are

1. vascular smooth muscle cells
  1. cardiac myocytes
  2. SA and AV nodal cells *

By binding to specific sites in Ca2+ channel subunits,CCBs * diminish the degree to which the Ca2+ channel pores open in response to voltage depolarization *

Answer 201

A

4 subunits a1, a2 b, gamma
a1 contains *pores *
No CCB binds to all pores –> * blockade is incomplete *

Answer 202

A

Dihydropyridine (DHP) – *Nifedipine * & related compounds
Effects mainly in the * vasculature *

Non-dihydropyridine (NDHP)
Phenylalkylamine - * Verapamil * & derivatives
Benzothiazepine - * Diltiazem * & derivatives
Effects mainly in
the * HEART *

Answer 203

A

Vasodilation
*more marked in arterial and arteriolar vessels than on veins *

Negative chronotropic and dromotropic effects
are seen on the SA and AV nodal conducting tissue (* NDHP agents only *).

Negative inotropic effects
are seen on myocardial cells; in the case of DHPs, this effect may be offset by reflex adrenergic stimulation after peripheral vasodilation.

Ratios of vasodilation to negative inotropy for the prototype CCBs were 10 : 1 for nifedipine, 1 : 1 for diltiazem and verapamil.

Answer 204

A

CCBs have *little or no effect on other smooth muscle *

CCBs may relax uterine smooth muscle and have been used in therapy for preterm contractions

Skeletal muscle does not respond to conventional CCBs *

Answer 205

A

*Systemic Hypertension

Angina Pectoris

Supraventricular Tachycardia

Post-infarct protection*

Answer 206

A

“slow” inward Ca2+ channels in nodal tissue are primarily affected 
Decrease SA automaticity -->Decrease HR
Decrease  AV conduction --> increase PR interval
cardiac depression (Decrease ventricular contractility and Decrease  HR)
no effect on ventricular Na+ conduction -->ineffective on ventricular arrhythmia

Answer 207

A

supraventricular tachycardia (IV – conversion, PO – maintenance) rate control in Afib
angina pectoris
hypertension

Answer 208

A

Headache, flushing, dizziness, ankle edema
*Constipation *
* Exacerbate CHF *
Hypotension (IV)
AV heart block in combination with β-blockers

Answer 209

A

Sick sinus syndrome
Pre-existing AV nodal disease
* WPW syndrome with Afib *
* Ventricular tachycardia *

Answer 210

A

Miscellaneous antiarrhythmics
Activates *A1receptor in SA & AV nodes * –> activates cAMP–independent, Ach/Ado-sensitive K+ channels –>
* SA node hyperpolarization and decrease firing rate *
* Shortening of AP duration of atrial cells *
* Depression of A-V conduction velocity *

Activates * A2receptor in vasculature * –> K+ channels
Increase endothelial Ca2+ –> increase NO
Smooth muscle hyperpolarization –>* vasodilation *

Stimulates pulmonary stretch receptors

Answer 211

A

*effective for acute conversion of paroxysmal supraventricular tachycardia caused by reentry involving accessory bypass pathways *. At a dose of 6mg, 60% of patients respond, and an additional 32% respond when given a 12-mg dose.

Answer 212

A

susceptibility to degradation and rapid plasma metabolism
* Must use as IV bolus to a central vein (brachial, antecubital)
t½=10-15 sec *
enzymatic metabolism in erythrocytes and vascular endothelium

Answer 213

A

hypotension, flushing, complete heart block, CNS effects, dyspnea

Answer 214

A

atropine * – produces a vagal block to increase HR
isoproterenol * – β1-stimulated increase in HR
Pacemaker *

Answer 215

A

vagal stimulation through carotid sinus massage or Valsalva maneuver *

Answer 216

A

Acetazolamide

Answer 217

A

: Mannitol

Answer 218

A

Furosemide (Lasix*),

Inhibit Na+-K+-2Cl-
cotransporter (NKCC) –>
inhibit reabsorption of solute
from TAL segments

Venodilation:decrease right atrial
pressure & pulmonary
capillary wedge pressure
within minutes (IV)

Answer 219

A

Hyponatremia
 *Hypokalemia*
 Hypocalcemia
 Hypomagnesia
 Ototoxicity
 Hyperuricemia

Answer 220

A

Chlorthalidone
 inhibit DCT *Na+-Cl- 
  cotransporter (NCC)*
  block coupled Na+ and Cl-  
  reabsorption

decrease Ca2+ excretion

vasorelaxation
(increase Ca2+-activated K+ channels)

Answer 221

A

Amiloride,

Answer 222

A

Spironolactone,

Answer 223

A

Antagonize aldosterone receptors in the renal collecting tubules

Decrease Na+ reabsorption –>natriuresis

Decrease loss of K+ in exchange for Na+

Answer 224

A

-Prevention of LV remodeling and cardiac fibrosis
Inhibition of matrix metalloproteinases
Inhibition of protein kinase C

- Prevention of sudden cardiac death
improve heart rate variability
reduce QT dispersion
reduce early morning rise in heart rate in HF patients
prevent severe hypokalemia

Hemodynamic effects
blood pressure reduction
modest diuresis and natriuresis
Vascular Effects
decrease vascular NAD(P)H oxidase activity
reduce the generation of reactive oxygen species
reverse endothelial dysfunction
increase nitric oxide bioactivity
retard the thrombotic response to injury

Answer 225

A

edema and hypertension (coadministered with thiazide or loop diuretics)
added to standard therapy of heart failure
primary hyperaldosteronism

 -refractory edema associated with secondary aldosteronism 
 cardiac failure
 hepatic cirrhosis
 nephrotic syndrome
 severe ascites

Answer 226

A

-Hyperkalemia
- Metabolic acidosis in cirrhotic patients
-Effects due to binding to other steroid receptors:
gynecomastia
impotence, decreased libido
hirsutism
deepening of the voice
menstrual irregularities

Answer 227

A

Block epithelial Na+ channels on principal cells in the late DCT and initial connecting tubule and the cortical collecting ducts –> modest natriuresis & prevention of K+ loss

Answer 228

A

used as K+-sparing agents in
hypokalemic alkalosis.

Used in combination with loop
diuretics / thiazides to prevent
hypokalemia caused by these agents

Answer 229

A

Hypertension - Less effective in patients with reduced
renal function

Control of edema: congestive heart failure …

Hypercalciuria

Nephrolithiasis

Nephrogenic Diabetes Insipidus: thiazides–>
increased renal Na+ reabsorption
recovery of Aquaporin-2 abundance
recovery of NCC, ENaC

Answer 230

A

inhibit DCT Na+-Cl-
cotransporter (NCC)
block coupled Na+ and Cl-
reabsorption

decrease Ca2+ excretion

vasorelaxation
(increase Ca2+-activated K+ channels)

Answer 231

A

Pulmonary edema
Congestive heart failure
Acute renal failure
Hypercalcemia: Saline + loop diuretics

Answer 232

A

increase fractional Ca2+ excretion by 30% by decreasing the lumen-positive transepithelial potential that promotes paracellular Ca2+ reabsorption

increase fractional Mg2+ excretion > 60% by decreasing voltage-dependent paracellular transport

Answer 233

A

ECV expansion –>

Risk of pulmonary edema in pts with heart failure
Hyponatremia: nausea, headache, vomiting
Hypernatremia: loss of water in excess of electrolytes

Answer 234

A

Anuria due to renal disease
Impaired liver function (urea)
Active cranial bleeding (mannitol & urea)

Answer 235

A

-Prophylaxis of acute renal failure

 expand the ECV
 maintain GFR
 increase  tubular fluid flow
 prevent tubule obstruction from shed cell        
  constituents or crystals
 reduce renal edema

Cerebral edema
Dialysis disequilibrium syndrome
Acute attacks of glaucoma

Answer 236

A

Osmotic Diuretics: freely filtered but poorly reabsorbed

increase tubular fluid osmotic pressure –> decrease tubular fluid reabsorption.

Answer 237

A

Hyperchloremic metabolic acidosis

Renal stones

Renal loss of K+

Answer 238

A

cirrhosis (increase plasma NH4+)

Answer 239

A

Glaucoma
Acute mountain sickness
To induce urinary alkalinization
Edema: combined with NKCC or NCC inhibitors

Answer 240

A

Blood pressure that is uncontrolled despite the use of three or more antihypertensive drugs, ideally taken at optimal doses, and of which one is a diuretic

Secondary causes are more common in the subset of patients with RHTN than in the general hypertensive population

Answer 241

A

Uncontrolled blood pressure that can be attributed to the “white coat” effect, poor adherence to medications, or incorrect blood pressure measurement techniques.

Answer 242

A

Treat with the intent of reducing risk of CV events and thereby reducing CV morbidity and mortality.

Answer 243

A

CO × TPR

Answer 244

A

Angiotensin-Converting Enzyme (ACE) Inhibitors

Angiotensin Receptor Blockers (ARB)

Calcium Channel Blockers (CCBs)

Diuretics & Aldosterone antagonists

Beta adrenergic blockers

Answer 245

A

a-adrenergic receptor blockers
Arterial vasodilators
Central a2 agonists
Direct renin inhibitor
Rauwolfia alkaloids

Answer 246

A

Captopril, Lisinopril, Fosinopril

ends in OPRIL

Answer 247

A

for uncomplicated HTN

Enhance the efficacy of diuretic drugs –>good combination

Answer 248

A

diabetes
chronic kidney disease
coronary artery disease
left ventricular dysfunction
previous ischemic stroke

Enhance the efficacy of diuretic drugs –> good combination

Answer 249

A

Cleared mostly by the kidney–> *reduce dose in kidney failure *

Fosinopril & spirapril cleared equally by liver and kidney

Elevated plasma renin activity causes hyperresponsive to ACEIs –> * reduce doses in pts with high plasma renin levels * (e.g., heart failure, Na+-depleted patients)

Answer 250

A

*Pregnancy *
Bilateral renal artery stenosis
History of angioedema

Answer 251

A

Low-normal potassium
* Prediabetes *
Albuminuria

Answer 252

A

High-normal K+

Hyperkalemia *
Volume depletion *

Answer 253

A

Hypotension (first dose, Na+-depleted, CHF, multi HTN Rx)
Coughing 5-20% – consider ARB when severe
Angioedema
Increased plasma K+
Acute renal failure
Fetopathic potential
Skin rash

Answer 254

A

Young & middle-aged Caucasians: good responders
Elderly African Americans: poorer responders
Dosing: PD, BID

Answer 255

A

Losartan, Valsartan, Candesartan

ends in SARTAN

Answer 256

A

* Inhibit Ang II-induced *
contraction of vascular smooth muscle
thirst
vasopressinrelease
aldosterone secretion 
release of adrenal catecholamines
enhancement of noradrenergic neurotransmission
increases in sympathetic tone
 changes in renal function
 cellular hypertrophy and hyperplasia

Answer 257

A

First-line or add-on therapy for uncomplicated hypertension – as effective as ACEIs

First-line therapy for compelling indications of 
Diabetes
Chronic kidney disease
Coronary artery disease
Left ventricular dysfunction

Commonly used as an alternative for patients with intolerance to ACE inhibitors

Answer 258

A

*Pregnancy *

Bilateral renal artery stenosis

Answer 259

A

Low-normal potassium

* Prediabetes *

Answer 260

A

High-normal K+

Hyperkalemia *
Volume depletion *

Answer 261

A

Nifedipine, Amlodipine, Felodipine

ends in DIPINE

Answer 262

A

*First-line or add-on therapy for uncomplicated hypertension *

Answer 263

A

Diabetes *

* Coronary artery disease *

Answer 264

A

Left ventricular dysfunction (all except amlodipine and felodipine)

Answer 265

A

Reynaud syndrome
Elderly patients with isolated systolic hypertension
Cyclosporine-induced hypertension

Answer 266

A

Peripheral edema

High-normal heart rate or tachycardia

Answer 267

A

Verapamil, Diltiazem

Answer 268

A

Vasodilation
*more marked in arterial and arteriolar vessels than on veins *

Negative chronotropic and dromotropic effectsare seen on the SA and AV nodal conducting tissue (* NDHP agents only *).

Negative inotropic effectsare seen on myocardial cells; in the case of DHPs, this effect may be offset by reflex adrenergic stimulation after peripheral vasodilation.

Ratios of vasodilation to negative inotropy for the prototype CCBs were 10 : 1 for nifedipine, 1 : 1 for diltiazem and verapamil.

Answer 269

A

First-line or add-on therapy for uncomplicated HTN
Add-on therapy for diabetes
Alternative to β-blockers in coronary artery disease

Answer 270

A

Second- or third-degree heart block

* Left ventricular dysfunction *

Answer 271

A

Reynaud syndrome

Migraine headache *
Arrhythmias *
High-normal heart rate or tachycardia *

Answer 272

A

Peripheral edema

* Low * -normal heart rate

Answer 273

A

Thiazides

Answer 274

A

First-line or add-on therapy for *uncomplicated HTN *
First-line therapy for compelling indications of
* left ventricular dysfunction *
* previous ischemic stroke *
Add-on therapy for diabetes or coronary artery disease

Answer 275

A

Prior allergic reactions to sulfa-type drugs
Gout
Hyponatremia
Hypokalemia

Answer 276

A

Osteoporosis or at increased risk for osteoporosis

High-normal K+

Answer 277

A

Gout
Prediabetes
Low-normal K+
Elevated fasting glucose

Answer 278

A

b-adrenergic receptor antagonists blockers for HTN

Answer 279

A

Add-on therapy for uncomplicated hypertension

First-line therapy for compelling indications of *
coronary artery disease *
left ventricular dysfunction *

Add-on therapy for diabetes

Answer 280

A

Migraine headache
Tachyarrhythmia
High-normal heart rate or tachycardia
Hyperthyroidism
Essential tremor
Preoperative hypertension

Answer 281

A

Spironolactone, Eplerenone

Answer 282

A

Add-on therapy for resistant hypertension
Add-on therapy for
coronary artery disease
left ventricular dysfunction

Answer 283

A

Low-normal potassium

Chronic kidney disease

Answer 284

A

High-normal potassium

Answer 285

A

Are agents that

are effective in lowering BP*
are approved for the treatment of hypertension*
have not been shown in clinical trials to reduce the risk of CV events*

Include
a-adrenergic receptor blockers
Arterial vasodilators
Central a2 agonists
Direct renin inhibitor
Rauwolfia alkaloids

Answer 286

A

Prazosin – Doxazosin – Terazosin

ends in AZOSIN

Answer 287

A

Efficacy: 15/10, monotherapy; 25/15 with diuretic

Added benefits: lowers LDL, TG and total cholesterol

Answer 288

A

mild tolerance development to antihypertensive effect
mild reflex tachycardia
sexual dysfunction

Answer 289

A

Clonidine (Catapres)

a-methyldopa (Aldomet)

Answer 290

A

Most commonly prescribed central a2-agonist
Limited by anticholinergic effects
Transdermal formulation available – useful for
labile HTN
Hospitalized pts who cannot take medications by mouth
Pts who are prone to early morning surges in BP

Can cause rebound hypertension if stopped abruptly
* Optimally used with a diuretic to diminish fluid retention *
Clonidine patch should be replaced once per week

Answer 291

A

Stimulate central a2 receptors –> decreased release of NE

Answer 292

A

Used almost exclusively in *gestational hypertension * and in the management of * chronic hypertension in pregnancy * because of its long history of safety

Answer 293

A

fewer anticholinergic side effects
Hepatotoxicity
Direct Coombs’ test

Answer 294

A

Hydralazine
Minoxidil (Loniten®)
Sodium Nitroprusside

Answer 295

A

decrease IP3-induced Ca2+ release from smooth muscle SR –> decrease contraction
Opens Ca2+-activated K+ channels in smooth muscle –> relaxation
Relaxes arterioles; little/no effect on veins;

Answer 296

A

often used as *add-on * therapy to manage * resistant HTN, *
particularly in patients with * severe chronic kidney disease *
Safe in pregnant women –>used for * gestational HTN *

Answer 297

A

Drug-induced * lupus * with long-term use
compensatory * tachycardia and Na+ retention –> * when used for chronic hypertension hydralazine * should be used in combination with both a diuretic and β-blocker or NDHP CCB * to mitigate these side effects

Answer 298

A

KATP channel opener: Activates ATP-dependent K+ channels –> *relaxes arteriolar VSMCs - * No effects on veins

Answer 299

A

Decrease BP
Increases blood flow to heart, skin (Rogaine®), skeletal muscle, GI tract, CNS
increase cardiac output (enhanced flow in regional vascular beds)
Increased renal blood flow

Answer 300

A

Oral use * only for severe, refractory hypertension *

* Use in combination with β-blockers and diuretics *

Answer 301

A

Fluid and salt retention
* Reflex increase in myocardial contractility *
Hypertrichosis

Answer 302

A

*Intravenous * agent used in hypertensive emergencies and the rapid management of CHF

Answer 303

A

donates NO ⇒ cGMP-mediated Ca2+ sequestration *
very potent vasodilator with rapid onset and short duration of action (1-10 minutes after cessation)
decreases both afterload and preload (venodilation) *

Answer 304

A

Aliskiren (Tekturna)

Answer 305

A

Binds directly to the catalytic site of renin  prevents it from cleaving angiotensinogen to generate angiotensin I

Answer 306

A

Approved as monotherapy or in combination therapy for HTN

As a new drug class and has not been shown to prevent CV events, it is not preferred as first-line therapy.

Demonstrated efficacy in lowering BP when used in combination with a thiazide, ACE inhibitor, ARB, or CCB

Answer 307

A

Can cause hyperkalemia in patients with CKD and diabetes or in those receiving a potassium-sparing diuretic, aldosterone antagonist, ACE inhibitor, or ARB

Can cause acute kidney failure in patients with severe bilateral renal artery stenosis or severe stenosis in an artery to a solitary kidney

Never usein pregnancy *

Starting dose can be halved in patients at risk for orthostatic hypotension

Answer 308

A

Reserpine

Answer 309

A

blocks transport of norepinephrine into storage granules

depletes norepinephrine from sympathetic nerve endings
- -> decrease sympathetic tone, decrease PVR –>decrease BP
depletes catecholamines in brain & myocardium
- -> sedation, depression, decrease cardiac output

Answer 310

A

rarely used in the treatment of HTN, in part because of perceived side effects.
the most effective use of reserpine is in combination with a thiazide diuretic, which can mitigate related sodium and water retention.

Answer 311

A

sedation, depression, decreased cardiac output, orthostatic hypotension
* strong sympatholytic effect results in increased parasympathetic activity*: nasal stuffiness, increased gastric acid secretion, diarrhea, and bradycardia.
if used in low doses, side effects are minimal

Answer 312

A

treatment with an RAS blocker and a diuretic.

Answer 313

A

Thiazide-type agents are preferred because of extensive evidence from randomized controlled outcome trials that they decrease risk for CV death and morbidity and also because of their wide availability and low cost.

Chlorthalidone is preferred by many hypertension specialists, because it is the agent used in major outcome trials that showed benefit.

Chlorthalidone is more potent, has a longer duration of action, and produces greater BP reductions than hydrochlorothiazide

Answer 314

A

Spironolactone (12.5 to 25mg/day) reduced BP significantly—by 25/12mmHg—after 6 mos in patients with RHTN who were receiving a triple-drug antihypertensive regimen that included an RAS blocker (ACE inhibitor or ARB) and a diuretic in full doses.

Spironolactone produces robust BP reductions when added to a regimen that includes an RAS blocker (ACE inhibitor or ARB).

Spironolactone is safe and is relatively well tolerated in RHTN patients. Adverse reactions to spironolactone are uncommon and occur in 4% to 7% of patients, usually at doses greater than 50mg/day, and are generally mild in severity

Answer 315

A

*Doxazosin *

Useful when added to multidrug antihypertensive regimens in RHTN.
Lowered BP by * 33/19mmHg *  76% of pts to lower BP below 140/90mm Hg
Doxazosin was well tolerated in these studies, and the development of overt heart failure was not seen.

Amiloride *
Directly blocks the epithelial sodium channel (ENaC)
Lowered the BP by * 31/15mmHg * when combined with hydrochlorothiazide patients (2.5 mg/25 mg) with RHTN and low plasma renin activity
Causes insignificant increases in serum K+ and creatinine
Otherwise well tolerated

Answer 316

A

Selective renal artery catheterization –> low-power radiofrequency treatments along the length of both main renal arteries to denervate both kidneys have been shown to be effective in reducing BP in patients with RHTN

Answer 317

A

Baroreflex Activation Therapy

Renal Sympathetic Denervation

Answer 318

A

*Extensive safety data

Answer 319

A

Appears to be safe; labetalol is preferred over other β-blockers because of a theoretical beneficial effect of α-blockade on uteroplacental blood flow

Answer 320

A

Extensive clinical experience

Answer 321

A

Increased risk of maternal hypotension and placental abruption when used acutely

Answer 322

A

Diuretics-May impair pregnancy-associated expansion in plasma volume

Atenolol-May impair fetal growth

Nitroprusside-Risk of fetal cyanide poisoning if used for >4h

Answer 323

A

ACE inhibitors-Multiple fetal anomalies

Angiotensin receptor antagonists-Similar risks as ACE inhibitors

Answer 324

A

release of bradykinin and adenosine onto nociceptive afferents

Answer 325

A

Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN

has NITR

Answer 326

A

Organic nitrates are *prodrugs * that must undergo * denitrification by mitochondrial aldehyde reductase * to yield NO

NO activates soluble GC, increasing * cGMP –> cGK-1 activation: *

increase mitochondrial Ca2+ uptake *
decrease Ca2+ influx *
Phosphorylates MLCK *

–>vasorelaxation

Answer 327

A

When given acutely, nitrates have potent hemodynamic and therapeutic effects. However, these effects were lost rapidly during sustained therapy, almost completely when significant plasma concentrations are present throughout the 24-hr period. Tolerance develops early, and cannot be overcome with higher doses

Mechanisms: controversial
Biotransformation hypothesis: SH- depletion (mALDH-2)
Neurohumoral hypothesis: reflex activation of the RAS system
Free radical hypothesis: sustained exposure to GTN –>increased production of free radicals from the endothelium
…
Nitrate effects could be maintained using dosing regimens that allow for a nitrate-free or low-nitrate concentration for several hours each day.

Answer 328

A

undergoes hepatic and intravascular metabolismwith a T1/2 ~ 1 – 4 minutes
Biologically active dinitrate metabolites T1/2 ~ 40 minutes
Very effective when given by sublingual (SL) or transdermal (TD) route (bypass first pass metabolism)
No evidence for efficacy when given orally

Answer 329

A

Rapidly metabolized, T1/2 ~ 40 minutes
Metabolites: isosorbide-2-mononitrate & isosorbide-5-mononitrate: T1/2 ~ 2 – 4 hrs
Available in phasic, sustained release form –> QD dosing –> avoid tolerance
Given PO or SL

Answer 330

A

*Does not undergo first-pass hepatic metabolism *– completely bioavailable
Metabolites: isosorbide-2-mononitrate & isosorbide-5-mononitrate: T1/2 ~ 2 – 4 hrs
Available in sustained, phasic release form –> QD dosing –> avoid tolerance

Answer 331

A

effects vary widely in different vascular beds
*Potent vasodilation in veins –>decrese ventricular volume and preload *
Dilate conduit arteries
* No effect on peripheral vascular resistance *.
Dilate epicardial coronary arteries
* Little or no effect on the coronary resistance vessels –> avoid coronary steal *
In patients with CAD, nitrates can dilate coronary stenoses and collateral vessels –>improve coronary blood flow

Answer 332

A

classic therapy for the treatment of acute attacks of angina
sublingual GTN & ISDN can be prescribed as a prophylactic therapy, taken before activity that would generally lead to angina

Answer 333

A

Effective in angina, increase exercise duration, decrease anginal frequency
Due to nitrate tolerance, dosing must allow for a low or nitrate-free period during the day
ISMN in a phasic-release formulation that provides effective plasma concentrations during the day but low concentrations during the night is effective in the therapy of exertional angina

Answer 334

A

Acute HF: organic nitrates (SL/IV) dramatically lower filling pressure without adverse effects on systemic BP. In acute HF and active ischemia, organic nitrates can be the therapy of choice.
Chronic heart failure.
ISDN and hydralazine combination: good in African-Americans with CHF, especially CHF that results from systolic dysfunction

Answer 335

A

Sublingual GTN is often used, but intravenous (IV) and transdermal formulations also have a role.
MOA likely includes dilation and prevention of constriction of epicardial coronary constriction and potential antiplatelet effects

Answer 336

A

Headaches: common, most pronounced early after initiation of therapy
* Hypotension * : more common with a rapid onset of action nitrates, such as sublingual GTN or short-acting isosorbide dinitrates, less with transdermal
sit or lie down at first dose during administration;
ISDN dose should be up-titrated over several days
Erythema or local edema at the site of transdermal application.
Methemoglobinemia: rare.

Answer 337

A

Cardiac Glycosides - Digitalis * (Digoxin)

Answer 338

A

Phosphodiesterase inhibitors * (Amrinone, Milrinone)

Answer 339

A

b adrenergic agonists * (review Autonomic Pharm slides 121-126)
(Isuprel, Dobutamine, Dopamine, Epinephrine, Norepinephrine)

Answer 340

A

b1 adrenergic antagonists *(review Autonomic Pharm slides 121-126)
(Metoprolol & Carvedilol)

Answer 341

A

Cardiac Glycosides

Answer 342

A

Positive inotropic effect –>
decrease EDV and decrease ESV
decrease pulmonary and systemic venous pressure
reflex decrease SANS –> (decrease preload, afterload & decrease HR)
Direct (+) vagal effect –>
increase vagal tone –> decrease A-V conduction
increase PR interval (longer ERP)
decrease APD (shorter QT)
*increase coronary flow (decrease hypertrophy)
decrease renal artery resistance (increase RBF ⇒ increase GFR ⇒ increase UO)
Proarrhythmic
ST depression (typical hockey stick)

Answer 343

A

T1/236-48 hours in patients with normal or near-normal renal function, permitting once-daily dosing.
Near steady-state blood levels are achieved ~7 days after initiation of maintenance therapy.
Excreted by the kidney – affected by rx that change RBF
Inactivated by Eubacterium Lentum (10% pop) –> rx tolerance.
Plasma concentration affected by many drugs:
CV rx: Antiarrhythmics class Ia & IV, spironolactone, vasodilators …
Cimetidine

Answer 344

A

‘digitalis intoxication’:
Low margin of safety * (TI susceptibility to side effects –> monitor plasma K+ *
* Arrhythmias *
Visual and neurological disturbances
CTZ stimulation induces * anorexia, nausea, vomiting

Answer 345

A

*Used very frequently in HF, especially CHF with AF*
Improves symptoms significantly
Improve patient’s quality of life
Reduce hospitalizations
Does not improve all-cause mortality -->
	no longer a first-line therapy for HF

Answer 346

A

cholestyramine*
digoxin immune Fab (des-IgG) [Digibind®]– *
- bind to both bound and free cardiac glycoside where it is sequestered in extracellular fluid and eliminated through the kidneys
- administered IV, immediate onset of action
- toxicity reversal within minutes
- clinical effects also reversed

Answer 347

A

Inamrinone & Milrinone

Answer 348

A

Directly stimulate myocardial contractility
Accelerate myocardial relaxation
Balanced arterial & venous dilation
–> decrease TPR, PVR, decrease LV, RV filling pressures

all increase CO

Answer 349

A

T1/2 ~ 2 – 3 hrs (inamrinone); 0.5 – 1 hr (milrinone), doubled in patients with severe CHF
Approved for short-term circulation support in advanced CHF

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