drugs Flashcards
(351 cards)
1
Q
<p></p>
<p>Methotrexate</p>
<p></p>
<p></p>
A
<p></p>
<ul>
<li>Antimetabolite</li>
<li>AntifolateChemotherapy (Folic acid analog)</li>
<li>Cytotoxic Agent (target all dividing cells)</li>
</ul>
<p></p>
<p></p>
2
Q
<p></p>
<p></p>
<p></p>
<p>Mechanism of action of methotrexate: What is the primary target?</p>
A
<p></p>
<p></p>
<p></p>
<p>Dihydrofolate reductase (DHFR) </p>
3
Q
<p></p>
<p></p>
<p></p>
<p>Mechanism of action of methotrexate</p>
A
<p></p>
<p></p>
<p></p>
<p>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
</p>
4
Q
<p><p><p><p>Methotrexate therapeutic uses </p></p></p></p>
A
<p><p><p><p>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.
</p></p></p></p>
5
Q
<p><p><p><p>Methotrexate therapeutic uses </p></p></p></p>
A
<p><p><p><p>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.
</p></p></p></p>
6
Q
<p></p>
<p></p>
<p></p>
<p>How do you reduce Methotrexate toxicity?</p>
A
<p></p>
<p></p>
<p></p>
<ul>
<li>Leucovorin rescue</li>
<li>Leucovorin is administered after and otherwise lethal dose of methotrexate is administered.</li>
</ul>
7
Q
<p><p><p><p>Methotrexate Resistance</p>
| </p></p></p>
A
<p><p><p><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>
</p></p></p>
8
Q
<p><p><p><p>Methotrexate Toxicities</p>
| </p></p></p>
A
<p><p><p><p>Nephrotoxicity</p>
| </p></p></p>
9
Q
<p><p><p><p>5-fluorouracil (5-FU) (4 things)</p>
| </p></p></p>
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>
10
Q
<p></p>
<p></p>
<p></p>
<p>Mechanism of action of 5-fluorouracil (5-FU)</p>
A
<p></p>
<p></p>
<p></p>
<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>
11
Q
<p><p><p><p>Capecitabine (4 things)</p>
| </p></p></p>
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>
12
Q
<p><p><p><p>Resistance to 5-FU can be associated with </p></p></p></p>
A
<p><p><p><p>amplification of thymidylate synthetase.
| </p></p></p></p>
13
Q
<p><p><p><p>5-FU used as a component of </p></p></p></p>
A
<p><p><p><p>chemotherapy regimens for breast cancer, head and neck cancers, colorectal, and gastrointestinal.
</p></p></p></p>
14
Q
<p><p><p><p>5-FU Rarely used as</p></p></p></p>
A
<p><p><p><p>a single agent
| </p></p></p></p>
15
Q
<p><p><p><p>5-FU Adverse effects </p></p></p></p>
A
<p><p><p><p>include oral and GI ulcers and bone marrow suppression
</p></p></p></p>
16
Q
<p><p><p><p>Capecitabine (3 things)</p></p></p></p>
A
<p><p><p><p>Antimetabolite
Pyrimidine analog
is a prodrug of 5-FU that had improved oral bioavailability allowing it to be given orally.
</p></p></p></p>
17
Q
<p><p><p><p>Most important antimetabolite to treat acute myelogenous leukemia (AML)</p>
</p></p></p>
A
<p><p><p><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>
</p></p></p>
18
Q
<p></p>
<p></p>
<p></p>
<p>Ara-CTP incorporation into DNA inhibits </p>
A
<p></p>
<p></p>
<p></p>
<p>DNA polymerase, thus halting elongation of DNA molecules</p>
19
Q
<p></p>
<p></p>
<p></p>
<p>Cytarabine (cytosine arabinoside, ara-C) Only active in </p>
A
<p></p>
<p></p>
<p></p>
<p>S-Phase</p>
20
Q
<p><p><p><p>Cytidine deaminase inactivates </p></p></p></p>
A
<p><p><p><p>ara-C.
| </p></p></p></p>
21
Q
<p><p><p><p>Cytarabine clinical toxicities</p>
| </p></p></p>
A
<p><p><p><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.<br></br>
</li>
</ul>
</p></p></p>
22
Q
<p></p>
<p></p>
<p>Gemcitabine resistance
| </p>
A
<p></p>
<p></p>
<p>Reduced activity of deoxycytidine kinase
Tumors increasing production of deoxycytidine
</p>
23
Q
<p><p><p><p>Cytarabine (3)</p>
| </p></p></p>
A
<p><p><p><ul> <li>Antimetabolite</li> <li>Pyrimidine analog</li> <li>Cytotoxic Agent</li> </ul> </p></p></p>
24
Q
<p></p>
<p></p>
<p></p>
<p>Gemcitabine(3)</p>
A
<p></p><p></p><p></p><ul> <li>Antimetabolite</li> <li>Pyrimidine analog</li> <li>Cytotoxic agent</li> </ul>
25
Gemcitabine Cytotoxic effects
- Incorporated into DNA, which inhibits synthesis and function
- Inhibits ribonucleotide reductase (reduces pools of dNTPs, which are necessary for DNA synthesis
26
Gemcitabine used in treatment of
a wide range of cancers including: pancreatic, non–small cell lung, ovarian, bladder, etc…
27
Gemcitabine resistance
|Reduced activity of deoxycytidine kinase Tumors increasing production of deoxycytidine
28
6-Thioguanine (6-TG) (4)
```
- Cytotoxic agent
- Antimetabolite
- Purine analog
- treatment of acute lymphoblastic leukemis.
29
6-Mercaptopurine (6-MP) (4)
```
- Cytotoxic agent
- antimetabolite
- Purine analog
- Treatment of acute lymphoblastic leukemia
30
6-Thioguanine (6-TG) 6-Mercaptopurine (6-MP)
- 6-MP was the first purine analog used in cancer chemotherapy
- Treatment of acute lymphoblastic leukemia (ALL)
- Largely replaced by newer antipurines fludarabine and cladribine
31
Mechanism of action of 6-TG (6-Thioguanine)
- activated to thio-GMP and thio-IMP hypoxanthine-guanine phospho- ribosyl transferase (HGPRT).
- Decreased activity of HGPRT common mechanism of resistance.
- Thiopurine methyltransferase (TPMT) inactivates 6-MP.
- Common gene variant (polymorphism) causes reduced TPMT activity.
- Can lead to life-threatening toxicity
32
Mechanism of action of 6-Mercaptopurine (6-MP)
- activated to thio-GMP and thio-IMP hypoxanthine-guanine phospho- ribosyl transferase (HGPRT).
- Decreased activity of HGPRT common mechanism of resistance.
- Thiopurine methyltransferase (TPMT) inactivates 6-MP.
- Common gene variant (polymorphism) causes reduced TPMT activity.
- Can lead to life-threatening toxicity
33
Fludarabine (4)
```
- Cytotoxic agent
- antimetabolite
- newer purine analog
- Commonly used to treat chronic lymphocytic leukemia (CLL) by itself or in combination with cyclophosphamide and rituximab.
34
Fludarabine Mechanism
- Deoxycytidine kinase activates drug in cells by converting it to the tri-phosphate form.
- Incorporated into DNA and RNA
- Inhibits DNA polymerase and ribonucleotide reductase (RNR)
- Inhibits RNA function, including mRNA translation into proteins
35
Fludarabine resistance
commonly caused be decreased activity of deoxycytidine kinase and drug efflux.
36
Cladribine (4)
```
- Cytotoxic Agent
- Newer purine analog
- antimetabolite
- Standard therapy for hairy cell leukemia (HCL) (curative intent) "when your HAIR gets wet it DRIPS"--> claDRIBine
37
Cladribine Mechanism
- Deoxycytidine kinase activates drug in cells by converting it to the tri-phosphate form.
- Incorporated into DNA
- Causes strand breaks
- Potent inhibitor of ribonucleotide reductase (RNR)
38
Cladribine resistance
commonly is associated with decreased activity of deoxycytidine kinase, drug efflux, and increased RNR expression
39
Methotrexate Mechanism
|Inhibits dihydrofolate reductase, which reduces precursors for RNA and DNA synthesis
40
5-fluorouracil (5-FU) | Mechanism
Incorporated into DNA and RNA, which inhibits synthesis and function Inhibits thymidylate synthetase, which reduces DNA precursors
41
Cytarabine (ara-C) | mechanism
Incorporated into DNA and RNA, which inhibits synthesis and function Inhibits DNA synthesis by inhibiting DNA polymerase
42
Gemcitabine Mechanism
Incorporated into DNA, which inhibits synthesis and function Inhibits ribonucleotide reductase (RNR), which reduces precursors for DNA
43
6-MP and 6-TG | Mechanism
Incorporated into DNA, which inhibits synthesis and function Reduce precursors for RNA and DNA by inhibiting purine synthesis
44
Cladribine | Mechanism
Incorporated into DNA Causes strand breaks Potent inhibitor of ribonucleotide reductase (RNR), which reduces DNA precursors
45
Cladribine | Mechanism
Incorporated into DNA Causes strand breaks Potent inhibitor of ribonucleotide reductase (RNR), which reduces DNA precursors
46
General mechanisms of alkylating agents
- Among the oldest and most useful class
- Reactions between alkyl groups on drug with nucleophilic groups on proteins and nucleic acids
- Most common binding site is seven-nitrogen group of guanine
- Cause DNA crosslinking and strand breakage
47
Alkylating agents
Cytotoxic cell cycle nonspecific agents (they are toxic in all stages of cell cycle)
48
Common alkylating agents
|- Nitrogen mustards
- Related to the ‘mustard gas’ used during the First World War
- Examples include: Mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide
- Nitrosoureas
- Carmustine (BCNU) and lomustine
49
Cyclophosphamide (4)
- Cytotoxic Agent
- Alkylating agent
- Nitrogen Mustard
- most commonly used alkylating agent in both solid tumors and hematological malignancies.
- Hemorrhagic cystitis caused by acrolein (5-10% of patients)
50
mesna
- Co-administration of mesna (with cyclophosphamide), a sulfhydryl compound, inactivates acrolein (cytotoxic to bladder cells).
- Reduces risk of hemorrhagic cystitis
51
Resistance to alkylating agents
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
52
Resistance to alkylating agents
|- 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
53
Non-classical alkylating agents
(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
54
Cisplatin
```
1st generation platinum agent cytotixic agent non-classical alkylating agent platinum analog
```
55
Carboplatin
```
2nd generation platinum agent cytotixic agent non-classical alkylating agent platinum analog
```
56
Oxaliplatin
3rd generation platinum agent cytotixic agent non-classical alkylating agent platinum analog
57
Non-classical alkylating agents | Commonly used to
ovarian, testicular, head and neck, bladder, esophagus, lung, and colon cancers
58
Cisplatin | adverse effects
Anaphylactic-like reactions (hypersensitivity reactions) Peripheral motor and sensory neuropathy Nephrotoxicity Can be significantly reduced by increasing hydration by co-administering intravenous saline
59
Cisplatin | adverse effects
Anaphylactic-like reactions (hypersensitivity reactions) Peripheral motor and sensory neuropathy Nephrotoxicity Can be significantly reduced by increasing hydration by co-administering intravenous saline
60
Vinblastine
- Cytotoxic agent
- Plant dericatives and similar compounds
- vinca alkaloid (from periwinkle plant)
- Antimicrotubule agents
61
Vincristine
- Cytotoxic agent
- Plant dericatives and similar compounds
- vinca alkaloid (from periwinkle plant)
- Antimicrotubule agents
62
Adverse effects of vincristine |
Mostly neurological (numbness and tingling in extremities, motor weakness)
63
Paclitaxel (taxol)
```
- Cytotoxic agent
- Plant derivatives and similar compounds
- Taxanes
- Antimicrotubule agents
64
Paclitaxel (taxol) mechanism
Paclitaxel kills tumor cells by arresting them in mitosis by preventing the depolymerization of microtubules.
65
Paclitaxel (taxol) adverse effect
peripheral neuropathy |
66
filgrastim
- (granulocyte-colony stimulating factor) used often with Paclitaxel to reduce myelosuppression
- Hypersensitivity allergic reactions occur in about 5 % of the patients receiving paclitaxel.
- This is largely prevented when patients are pretreated with dexamethasone and anti-histamines.
67
irinotecan
- cytotoxic agent
- plant derivative and similar compound
- camptothecins analog
- induce cytotoxicity by inhibiting topoisomerase I (prevents repair of cuts leading to DNA damage).
68
Etoposide
cytotoxic agent
plant derivative and similar compound
other
is a class II topoisomerase inhibitor
69
Etoposide
- cytotoxic agent
- plant derivative and similar compound
- other
- is a class II topoisomerase inhibitor
70
Doxorubicin
cytotoxic antibiotics
| anthracyclines (anthracycline antibiotic)
71
Doxorubicin mech
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,
72
Doxorubicin Adverse effect
Irreversible cardiomyopathy
73
Bleomycin
Cytotoxic Anitibiotics
74
Bleomycin mech
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)
75
Bleomycin used in
curative combination chemotherapy regimens for testicular cancer and Hodgkin's disease
76
Bleomycin Adverse effect
Dose-limiting adverse side effect is pulmonary toxicity
| Effects are cumulative and irreversible
77
The majority of cytotoxic agents induce
myelosuppression
78
Prednisone
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
79
dexamethasone
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
80
Tamoxifen
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
81
Flutamide
Androgen receptor antagonists that are useful for the treatment of prostate cancer
These drugs prevent dihydrotestosterone from binding to androgen receptors
82
Anastrozole
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.
83
Anastrozole
| Used to treat
estrogen-sensitive (estrogen receptor-positive) breast tumors in post-menopausal women
84
Trastuzumab (Herceptin)
monoclonal antibodies
HER-2 Inhibitor
Used to treat breast cancer with HER-2 amplified
First monoclonal antibody approved for the treatment of solid tumors
85
Trastuzumab (Herceptin) Toxicities
Most serious is cardiotoxicity
86
Trastuzumab (Herceptin) Toxicities
Most serious is cardiotoxicity
87
Cetuximab
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
88
Bevacizumab
Bevacizumab is an monoclonal antibody directed against vascular endothelial growth factor (VEGF).
89
Bevacizumab Mech
binds to VEGF, which prevents VEGF from binding to VEGFR (prevents angiogenesis).
90
Bevacizumab Uses
Colorectal cancer in combination with capecitabine and oxaliplatin
It is also used in combinations with other drugs to treat metastatic breast and colorectal cancer.
91
Lapatinib
Small Molecule tyrosine kinase inhibitor
92
Lapatinib Mech
Small molecule that inhibits both EGFR and HER-2 kinase activity
93
Lapatinib Used in combination
with capecitabine to treat HER2-amplified, trastuzumab-refractory breast cancer
94
Erlotinib
Small molecule turosine kinase inhibitor
Oral small-molecule EGFR inhibitor
ATP competitive inhibitor
95
Erlotinib First-line treatment of
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.
96
Imatinib
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.
97
Chronic myelogenous leukemia (CML) is caused by
the Philadelphia chromosome translocation.
Fusion protein between BCR and the ABL tyrosine kinase
Leads to constitutive activation of ABL
98
Imatinib Resistance mechanisms
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
99
Asparaginase
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.
100
Asparaginase adverse effect
allergic hypersensitivity reaction (fever, chills, rash, hives)
Can become severe causing respiratory failure and hypotension
101
Bortezomib
(proteasome inhibitor)
102
Bortezomib Mech
By inhibiting the proteasome, it elevates levels of p53
Can also reduce levels of a protein that normally inhibits apoptosis called NF-kappaB
103
Bortezomib Approved for treatment of
patients with relapsed or refractory multiple myeloma
104
Bortezomib Adverse effects:
Peripheral neuropathy is most the most chronic toxicity
105
Temsirolimus
Used to treat renal cell carcinoma
Inhibition of mTOR complex 1 (mTORC1) reduces protein translation, promotes cell cycle inhibition, and promotes apoptosis.
106
Temsirolimus Resistance mechanism
mTOR forms a complex called mTOR complex 2 (mTORC2)
| mTORC2 is not inhibited by temsirolimus
107
Adverse effect: Nephrotoxic
cisplatin, methotrexate
108
Adverse effect: Neurotoxic (peripheral neuropathies, cerebellar syndrome, and others
vincristine, cytarabine (ara C), cisplatin, bortezomib, paclitaxel
109
Adverse effect: Cardiac toxicity
doxorubicin,
| trastuzumab
110
Adverse effect: Pulmonary
| toxicities
methotrexate, bleomycin,
alkylating
agents
111
Adverse effect: Bladder toxicity (hemorrhagic
| cystitis)
cyclophosphamide
112
Adverse effect: Hypersensitivity reactions
asparaginase,
| paclitaxel
113
Mechlorethamine
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)
"
114
Oxaliplatin
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
115
dexrazoxane
Iron chelator
| used with Doxorubicin to reduce cardiotoxicity
116
Aspirin (mechanism of action)
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).
117
Dipyridamole
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.
118
Clopidogrel
irreversible P2Y12 inhibitors that are prodrugs that have to be activated by metabolism in the liver
has to be activated by CYP2C19
119
prasugrel
irreversible P2Y12 inhibitors that are prodrugs that have to be activated by metabolism in the liver
120
Ticagrelor
P2Y12 inhibitors
do not need to be metabolized to become activated.
Is reversible
More rapid coagulation recovery upon discontinuation
121
cangrelor
P2Y12 inhibitors
do not need to be metabolized to become activated.
Is reversible
More rapid coagulation recovery upon discontinuation
122
Abciximab
typically used as adjunct therapy in patients undergoing PCI to prevent ischemic complications.
Sometimes combined with heparin and aspirin as adjunct to PCI
123
eptifibatide
typically used as adjunct therapy in patients undergoing PCI to prevent ischemic complications.
Sometimes combined with heparin and aspirin as adjunct to PCI
124
Tirofiban and eptifibatide
used in patients with unstable angina.
125
Abciximab Mech
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
126
Eptifibatide Mech
a peptide that binds to and inhibits GPIIb/IIIa.
127
Tirofiban Mech
a nonpeptidic small molecule that binds to and inhibits GPIIb/IIIa.
128
Both _______ and _______ have a lower risk of producing thrombocytopenia than abciximab.
eptifibatide and tirofiban
129
Vorapaxar
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
130
Indirect inhibitors of thrombin and/or Factor Xa (anticoagulant effect exerted through binding to antithrombin)
Heparin (parenteral)
Enoxaparin (low molecular weight heparin) (parenteral) *
Fondaparinux (parenteral) *
131
Direct thrombin inhibitors
Lepirudin (parenteral)
Bivalirudin (parenteral)
Argatroban (parenteral)
Dabigatran (oral)**
132
Direct factor Xa inhibitors
Rivaroxaban (oral) **
| Apixaban (oral) **
133
Vitamin K antagonists (VKAs)
Warfarin (oral)
134
Heparin sulfate
is a proteoglycan found on the surface of vascular endothelial cells.
Binds to antithrombin to increase inhibition of factor Xa and thrombin
135
Heparin (mechanism of action)
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 .
136
Heparin is a family
sulfated-polysaccharides of varying molecular weights found in mast cells and thought to be required for histamine storage.
Not normally found in the plasma
137
Heparin can be isolated from
tissues rich in mast cells (usually animal intestines or lungs)
138
heparin Administered
parenterally to inhibit coagulation
139
Heparin (pharmacokinetics)
Heparin has to be administered parenterally.
To achieve anticoagulant effect rapidly, heparin is usually administered intravenously.
140
After heparin enters circulation
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.
141
Heparin can be cleared by 2 mechanisms
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).
142
Heparin monitoring
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.
143
Heparin (adverse effects)
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)
144
Heparin-induced thrombocytopenia type II
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
145
enoxaparin.
```
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.
146
Main clearance of LMWH
by kidney
| Thus, LMWH is contraindicated for use in patients with severe renal insufficiency.
147
Fondaparinux
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)
148
Fondaparinux Main clearance
by kidney
| Fondaparinux is contraindicated in patients with severe renal insufficiency
149
Lepirudin
recombinant from of hirudin.(a compound isolated from the leach, was the first DTI to be used.)
150
Bivalirudin and lepirudin
bind at both the fibrin binding site and the active site of thrombin (bivalent).
151
Argatroban and dabigatran
are small molecular inhibitors that bind only to active site of thrombin (univalent).
152
Bivalirudin, lepirudin, and argatroban
Parenteral:
153
Dabigatran
oral
154
DTIs versus heparin
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
155
Direct thrombin inhibitors (DTIs)
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
156
Warfarin (clinical use)
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
157
Warfarin is a small lipid soluble derivative of
vitamin K.
Warfarin competes with vitamin K for vitamin K reductase (VCORC1).
158
Mechanism of action of warfarin
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
159
Warfarin (Coumadin) is an
anticoagulant that works by inhibiting vitamin K reduction leading to a decrease in activation of Factors II, VII , IX and X.
160
Warfarin (pharmacokinetics)
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)
161
Drugs that interact with warfarin
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
162
Other factors that can effect the anticoagulant effect of warfarin
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).
163
Warfarin (adverse effects)
```
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.
164
Warfarin antagonists
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.
165
Rivaroxaban
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.
166
Apixaban
New oral anticoagulants
| Xa inhibitor
167
Dabigatran
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)
168
New oral anticoagulants
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.
169
Alteplase
recombinant human t-PA
170
Clinical uses of fibrinolytic drugs
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 12 h of onset (the earlier the better!).
Other uses include:
Acute thrombotic stroke within 3 h 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)
171
Tirofiban used
used in patients with unstable angina.
172
Class I Agents
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
173
Class Ia Agents – General
‘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
174
Class Ia Agents
Quinidine, Procainamide, Disopyramide
175
Quinidine Mechanisms of Action
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
176
Quinidine only used in
refractory patients to
Convert symptomatic AF or flutter
Prevent recurrences of AF
Treat documented, life-threatening ventricular arrhythmias
177
Quinidine Adverse effects
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)
178
Procainamide
| Mechanisms of Action
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
179
Procainamide
| Clinical Applications
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
180
Procainamide
| Adverse Effects
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
181
Class Ib Agents – General
‘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
182
Class Ib Agents
Lidocaine, Phenytoin, Mexiletine, Tocainide
183
Lidocaine
| Mechanism of Action
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
184
Lidocaine
Clinical Applications
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
185
Lidocaine
| Clinical Pharmacology
Extensive first-pass hepatic metabolism IV use.
| need multiple loading doses and a maintenance infusion
186
Class Ic Agents – General
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)
187
Class Ic Agents
Moricizine, Flecainide, Propafenone
188
Propafenone
| Mechanism of action
Strong inhibitor of Na+ channel
| Can inhibits b-adrenergic R: marked structural similarity to propranolol
189
Propafenone
| Clinical applications
used primarily to treat atrial arrhythmias, PSVT, and ventricular arrhythmias in patients with no or minimal heart disease and preserved ventricular function
190
Flecainide
Mechanism of action
potent Na+ channel blockade -->prolongs phase 0 and widens QRS
markedly slows intraventricular conduction
191
Flecainide
| Clinical applications
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*
192
Class II Agents – General -b-adrenergic antagonists
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
193
Class III Agents – General
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
194
Class III Agents
Dronedarone, Amiodarone, Sotalol, Ibutilide, Dofetilide - DASID
195
Amiodarone
| Mechanism of Action
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
196
Amiodarone
| Clinical Applications
*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 lidocaine as first-line therapy for out-of-hospital cardiac arrest *
197
Amiodarone
| Clinical Pharmacology
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
198
Amiodarone
| Adverse Reactions
*IV > 5 mg/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
199
Class IV Agents – General
*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 *
200
Class IV Agents
Verapamil, Diltiazem
201
Calcium Channel Blockers (CCBs) - General
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
2. cardiac myocytes
3. 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 *
202
CCBs - L-type Ca2+ channel a1 subunit
- 4 subunits a1, a2 b, gamma
- a1 contains *pores *
No CCB binds to all pores --> * blockade is incomplete *
203
CCBs - Main classes
Dihydropyridine (DHP) – *Nifedipine * & related compounds
Effects mainly in the * vasculature *
Non-dihydropyridine (NDHP)
Phenylalkylamine - * Verapamil * & derivatives
Benzothiazepine - * Diltiazem * & derivatives
Effects mainly in
the * HEART *
204
CCBs - Major Cardiovascular Actions
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.
205
CCBs – Non-cardiovascular Effects
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 *
206
CCBs – Main Clinical Applications
*Systemic Hypertension
Angina Pectoris
Supraventricular Tachycardia
Post-infarct protection*
207
Verapamil
| Mechanisms of action
```
“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
```
208
Verapamil
| Clinical Applications
*supraventricular tachycardia (IV – conversion, PO – maintenance) rate control in Afib*
angina pectoris
hypertension
209
Verapamil
| Adverse Effects:
Headache, flushing, dizziness, ankle edema
*Constipation *
* Exacerbate CHF *
Hypotension (IV)
AV heart block in combination with β-blockers
210
Verapamil
| Contraindications
Sick sinus syndrome
Pre-existing AV nodal disease
* WPW syndrome with Afib *
* Ventricular tachycardia *
211
Adenosine
| Mechanism of Action
Miscellaneous antiarrhythmics
Activates *A1 receptor 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 * A2 receptor in vasculature * --> K+ channels
Increase endothelial Ca2+ --> increase NO
Smooth muscle hyperpolarization -->* vasodilation *
Stimulates pulmonary stretch receptors
212
Adenosine
Clinical Applications
*effective for acute conversion of paroxysmal supraventricular tachycardia caused by reentry involving accessory bypass pathways *. At a dose of 6 mg, 60% of patients respond, and an additional 32% respond when given a 12-mg dose.
213
Adenosine
| Clinical pharmacology
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
214
Adenosine
| Adverse Effects
hypotension, flushing, complete heart block, CNS effects, dyspnea
215
Management of Other Arrhythmias
| Bradycardia
* atropine * – produces a vagal block to increase HR
* isoproterenol * – β1-stimulated increase in HR
* Pacemaker *
216
Management of Other Arrhythmias
| Sinus Tachycardia, PSVT
* vagal stimulation through carotid sinus massage or Valsalva maneuver *
217
Carbonic Anhydrase Inhibitors
Acetazolamide
218
Osmotic Diuretics
: Mannitol
219
NKCC inhibitors (loop diuretics)
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)
220
Furosemide (Lasix*),
| Adverse effects
```
Hyponatremia
*Hypokalemia*
Hypocalcemia
Hypomagnesia
Ototoxicity
Hyperuricemia
```
221
NCC Inhibitors (Thiazides & Sulfonamides)
```
Chlorthalidone
inhibit DCT *Na+-Cl-
cotransporter (NCC)*
block coupled Na+ and Cl-
reabsorption
```
decrease Ca2+ excretion
vasorelaxation
(increase Ca2+-activated K+ channels)
222
Inhibitors of Renal Epithelial Na+ channels
Amiloride,
223
Aldosterone-Receptor Antagonists
Spironolactone,
224
Spironolactone,
Antagonize aldosterone receptors in the renal collecting tubules
Decrease Na+ reabsorption -->natriuresis
Decrease loss of K+ in exchange for Na+
225
Spironolactone, Therapeutic Effects
-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
226
Spironolactone,
| Clinical Applications
- 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
```
227
Spironolactone,
| Adverse Effects
-*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
228
Amiloride,
| ACTIONS
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
229
: Amiloride,
| CLINICAL INDICATIONS
used as K+-sparing agents in
hypokalemic alkalosis.
Used in combination with loop
diuretics / thiazides to prevent
hypokalemia caused by these agents
230
Chlorthalidone
| Clinical Applications
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
231
Chlorthalidone
| Mechanisms of Action
inhibit DCT *Na+-Cl-
cotransporter (NCC)*
block coupled Na+ and Cl-
reabsorption
decrease Ca2+ excretion
vasorelaxation
(increase Ca2+-activated K+ channels)
232
Furosemide (Lasix*),
| Clinical Indications
Pulmonary edema
Congestive heart failure
Acute renal failure
Hypercalcemia: Saline + loop diuretics
233
Furosemide (Lasix*),
| Mechanisms of action
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
234
Mannitol
| Adverse effects:
ECV expansion -->
Risk of pulmonary edema in pts with heart failure
Hyponatremia: nausea, headache, vomiting
Hypernatremia: loss of water in excess of electrolytes
235
Mannitol
| Contraindications:
Anuria due to renal disease
Impaired liver function (urea)
Active cranial bleeding (mannitol & urea)
236
Mannitol
| Clinical Applications
-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
237
Mannitol,
| Mechanisms & Sites of Action
Osmotic Diuretics: freely filtered but poorly reabsorbed
increase tubular fluid osmotic pressure --> decrease tubular fluid reabsorption.
238
Acetazolamide
| Adverse effects:
Hyperchloremic metabolic acidosis
Renal stones
Renal loss of K+
239
: Acetazolamide
| Contraindications
cirrhosis (increase plasma NH4+)
240
Acetazolamide
| Clinical Indications
Glaucoma
Acute mountain sickness
To induce urinary alkalinization
Edema: combined with NKCC or NCC inhibitors
241
Resistant Hypertension
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
242
Pseudo-resistant Hypertension
Uncontrolled blood pressure that can be attributed to the “white coat” effect, poor adherence to medications, or incorrect blood pressure measurement techniques.
243
Principle of Treatment for Hypertension
Treat with the intent of reducing risk of CV events and thereby reducing CV morbidity and mortality.
244
MAP
CO × TPR
245
CO
HR × SV
246
Drug Groups Used in Hypertension
Angiotensin-Converting Enzyme (ACE) Inhibitors
Angiotensin Receptor Blockers (ARB)
Calcium Channel Blockers (CCBs)
Diuretics & Aldosterone antagonists
Beta adrenergic blockers
247
Drug Groups Used in Hypertension
| Other agents
```
a-adrenergic receptor blockers
Arterial vasodilators
Central a2 agonists
Direct renin inhibitor
Rauwolfia alkaloids
```
248
Angiotensin-Converting Enzyme Inhibitors for HTN
Captopril, Lisinopril, Fosinopril
ends in OPRIL
249
Captopril, Lisinopril, Fosinopril
| First-line or add-on therapy
for uncomplicated HTN
Enhance the efficacy of diuretic drugs -->good combination
250
Captopril, Lisinopril, Fosinopril
| First-line therapy for compelling indications of
```
diabetes
chronic kidney disease
coronary artery disease
left ventricular dysfunction
previous ischemic stroke
```
Enhance the efficacy of diuretic drugs --> good combination
251
Captopril, Lisinopril, Fosinopril
| Clinical Pharmacology
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)
252
Captopril, Lisinopril, Fosinopril
| Avoid use
*Pregnancy *
Bilateral renal artery stenosis
History of angioedema
253
Captopril, Lisinopril, Fosinopril
| Situations with potentially favorable effects
Low-normal potassium
* Prediabetes *
Albuminuria
254
Captopril, Lisinopril, Fosinopril
| Situations with potentially unfavorable effects
High-normal K+
* Hyperkalemia *
* Volume depletion *
255
Captopril, Lisinopril, Fosinopril
| Adverse Effects
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
256
Captopril, Lisinopril, Fosinopril
| Pharmacogenetics & PK
Young & middle-aged Caucasians: good responders
Elderly African Americans: poorer responders
Dosing: PD, BID
257
Angiotensin Receptor 1 Blockers for HTN
Losartan, Valsartan, Candesartan
ends in SARTAN
258
Losartan, Valsartan, Candesartan
| Effects
```
* Inhibit Ang II-induced *
contraction of vascular smooth muscle
thirst
vasopressin release
aldosterone secretion
release of adrenal catecholamines
enhancement of noradrenergic neurotransmission
increases in sympathetic tone
changes in renal function
cellular hypertrophy and hyperplasia
```
259
Losartan, Valsartan, Candesartan
| Role in antihypertensive therapy
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*
260
Losartan, Valsartan, Candesartan
| Avoid use
*Pregnancy *
| Bilateral renal artery stenosis
261
Losartan, Valsartan, Candesartan
| Situations with potentially favorable effects
Low-normal potassium
| * Prediabetes *
262
Losartan, Valsartan, Candesartan
| Situations with potentially unfavorable effects
High-normal K+
* Hyperkalemia *
* Volume depletion *
263
Dihydropyridine Calcium Channel Blockers for HTN
Nifedipine, Amlodipine, Felodipine
ends in DIPINE
264
Nifedipine, Amlodipine, Felodipine
| Role in antihypertensive therapy
*First-line or add-on therapy for uncomplicated hypertension *
265
Nifedipine, Amlodipine, Felodipine
| Add-on therapy for
* Diabetes *
| * Coronary artery disease *
266
Nifedipine, Amlodipine, Felodipine
| Avoid use
Left ventricular dysfunction (all except amlodipine and felodipine)
267
Nifedipine, Amlodipine, Felodipine
| Situations with potentially favorable effects
Reynaud syndrome
*Elderly patients with isolated systolic hypertension*
Cyclosporine-induced hypertension
268
Nifedipine, Amlodipine, Felodipine
| Situations with potentially unfavorable effects
Peripheral edema
| *High-normal heart rate or tachycardia*
269
Non-dihydropyridine Calcium Channel Blockers for HTN
Verapamil, Diltiazem
270
Verapamil, Diltiazem
| Mechanism of Action
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.
271
Verapamil, Diltiazem
| Role in antihypertensive therapy
First-line or add-on therapy for uncomplicated HTN
Add-on therapy for diabetes
Alternative to β-blockers in *coronary artery disease*
272
Verapamil, Diltiazem
| Avoid Use
Second- or third-degree heart block
| * Left ventricular dysfunction *
273
Verapamil, Diltiazem
| Situation with potentially favorable effects
Reynaud syndrome
* Migraine headache *
* Arrhythmias *
* High-normal heart rate or tachycardia *
274
Verapamil, Diltiazem
| Situation with potentially unfavorable effects
Peripheral edema
| * Low * -normal heart rate
275
diuretics for HTN
Thiazides
276
Thiazides
| Role in antihypertensive therapy
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
277
Thiazides
| Avoid use
Prior allergic reactions to sulfa-type drugs
Gout
Hyponatremia
Hypokalemia
278
Thiazides
| Situation with potentially favorable effects
Osteoporosis or at increased risk for osteoporosis
| High-normal K+
279
Thiazides
| Situation with potentially unfavorable effects
Gout
Prediabetes
Low-normal K+
Elevated fasting glucose
280
b-adrenergic receptor antagonists blockers for HTN
b-adrenergic receptor antagonists blockers for HTN
281
Propranolol, Metoprolol, Pindolol, Labetalol
| Role in antihypertensive therapy
Add-on therapy for uncomplicated hypertension
* First-line therapy for compelling indications of *
* coronary artery disease *
* left ventricular dysfunction *
Add-on therapy for diabetes
282
Propranolol, Metoprolol, Pindolol, Labetalol
| Situation with potentially favorable effects
```
Migraine headache
Tachyarrhythmia
High-normal heart rate or tachycardia
Hyperthyroidism
Essential tremor
Preoperative hypertension
```
283
Aldosterone Antagonists for HTN
Spironolactone, Eplerenone
284
Spironolactone, Eplerenone
| Role in antihypertensive therapy
Add-on therapy for resistant hypertension
Add-on therapy for
coronary artery disease
left ventricular dysfunction
285
Spironolactone, Eplerenone
| Situation with potentially favorable effects
Low-normal potassium
| Chronic kidney disease
286
Spironolactone, Eplerenone
| Situation with potentially unfavorable effects
High-normal potassium
287
Other Agents for HTN
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
```
288
Other Agents for HTN - a1-adrenergic receptor blockers
Prazosin – Doxazosin – Terazosin
ends in AZOSIN
289
Prazosin – Doxazosin – Terazosin
| Role in antihypertensive therapy
Efficacy: 15/10, monotherapy; 25/15 with diuretic
| Added benefits: lowers LDL, TG and total cholesterol
290
Prazosin – Doxazosin – Terazosin
| Adverse Effects
mild tolerance development to antihypertensive effect
mild reflex tachycardia
sexual dysfunction
291
Other Agents for HTN - Central a2 agonists
Clonidine (Catapres)
| a-methyldopa (Aldomet)
292
Clonidine (Catapres)
| Role in antihypertensive therapy
*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
293
a-methyldopa (Aldomet)
| Mechanism of action
Stimulate central a2 receptors --> decreased release of NE
294
a-methyldopa (Aldomet)
| Role in antihypertensive therapy
Used almost exclusively in *gestational hypertension * and in the management of * chronic hypertension in pregnancy * because of its long history of safety
295
a-methyldopa (Aldomet)
| Adverse effects
fewer anticholinergic side effects
Hepatotoxicity
Direct Coombs’ test
296
Other Agents for HTN – Arterial Vasodilators
Hydralazine
Minoxidil (Loniten®)
Sodium Nitroprusside
297
Hydralazine
| Actions
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;
298
Hydralazine
| Role in antihypertensive therapy
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 *
299
Hydralazine
| Adverse Effects
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
300
Minoxidil (Loniten®)
| Mechanism of action
KATP channel opener: Activates ATP-dependent K+ channels --> *relaxes arteriolar VSMCs - * No effects on veins
301
Minoxidil (Loniten®)
| Cardiovascular effects
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
302
Minoxidil (Loniten®)
| Role in antihypertensive therapy
Oral use * only for severe, refractory hypertension *
| * Use in combination with β-blockers and diuretics *
303
Minoxidil (Loniten®)
| Adverse effects
Fluid and salt retention
* Reflex increase in myocardial contractility *
Hypertrichosis
304
Sodium Nitroprusside
*Intravenous * agent used in hypertensive emergencies and the rapid management of CHF
305
Sodium Nitroprusside
| MOA:
* 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) *
306
Other Agents for HTN – Direct renin inhibitor
Aliskiren (Tekturna)
307
Aliskiren (Tekturna)
| Mechanism of action
Binds directly to the catalytic site of renin prevents it from cleaving angiotensinogen to generate angiotensin I
308
Aliskiren (Tekturna)
| Role in antihypertensive therapy
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*
309
Aliskiren (Tekturna)
| Adverse effects & Precautions
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 use in pregnancy *
Starting dose can be halved in patients at risk for orthostatic hypotension
310
Other Agents for HTN – Rauwolfia Alkaloids
Reserpine
311
Reserpine
| Mechanisms of action
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
312
Reserpine
| Role in antihypertensive therapy
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.
313
Reserpine
| Side effects
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
314
RHTN patients with or without evidence of aldosterone excess have been shown to be fluid overloaded despite
treatment with an RAS blocker and a diuretic.
315
Resistant Hypertension – Pharmacologic Therapy
| Diuretics
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
316
Resistant Hypertension – Pharmacologic Therapy
| Mineralocorticoid Receptor Antagonists
*Spironolactone* (12.5 to 25 mg/day) reduced BP significantly—by 25/12 mm Hg—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 50 mg/day, and are generally mild in severity
317
Resistant Hypertension – Pharmacologic Therapy
| Other Antihypertensive Agents (2)
*Doxazosin *
Useful when added to multidrug antihypertensive regimens in RHTN.
Lowered BP by * 33/19 mm Hg * 76% of pts to lower BP below 140/90 mm 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 * 31/15 mm Hg * 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
318
Renal Sympathetic Denervation
*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*
319
Resistant Hypertension – Other Treatment Modalities
Baroreflex Activation Therapy
| Renal Sympathetic Denervation
320
Methyldopa (PO; B)
Hypertension in Pregnancy
ADVANTAGES
*Extensive safety data
321
Hypertension in Pregnancy
Labetalol
(IV or PO; C)
ADVANTAGES
*Appears to be safe; labetalol is preferred over other β-blockers because of a theoretical beneficial effect of α-blockade on uteroplacental blood flow*
322
Hypertension in Pregnancy
Hydralazine
(PO or IV; C)
ADVANTAGES
*Extensive clinical experience*
323
Hypertension in Pregnancy
Hydralazine
(PO or IV; C)
DISADVANTAGES
Increased *risk of maternal hypotension* and placental abruption when used acutely
324
Hypertension in Pregnancy
| Drugs generally avoided
Diuretics-May impair pregnancy-associated expansion in plasma volume
Atenolol-May impair fetal growth
Nitroprusside-Risk of fetal cyanide poisoning if used for >4 h
325
Hypertension in Pregnancy
Drugs
Contraindicated
ACE inhibitors-Multiple fetal anomalies
Angiotensin receptor antagonists-Similar risks as ACE inhibitors
326
Anginal pain is usually due to
release of bradykinin and adenosine onto nociceptive afferents
327
Organic Nitrates for Myocardial Ischemia
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN
has NITR
328
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN
Mechanism of actions
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
329
Nitrate Tolerance
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.*
330
Nitroglycerin
undergoes *hepatic and intravascular metabolism*with 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
331
Isosorbide Dinitrate:
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
332
Isosorbide mononitrate:
*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*
333
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN
Pharmacodynamic Effects
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
334
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN)
Therapeutic Uses
Sublingual Nitrates
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
335
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN)
Therapeutic Uses
Long-Acting Nitrates
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
336
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN)
Therapeutic Uses
Congestive Heart Failure
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
337
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN)
Therapeutic Uses
Unstable angina and acute myocardial infarction (MI)
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
338
Nitroglycerin (GTN), Isosorbide Dinitrate (ISDN), Isosorbide Mononitrate (ISMN)
Side Effects
*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.
339
*Practical * approaches to increase intrinsic myocardial contractility
Increase cytosolic Ca2+
* Cardiac Glycosides - Digitalis * (Digoxin)
340
*Practical * approaches to increase intrinsic myocardial contractility
. Increase myocardial cAMP
* Phosphodiesterase inhibitors * (Amrinone, Milrinone)
341
*Practical * approaches to increase intrinsic myocardial contractility
Agonism at b1 receptors
* b adrenergic agonists * (review Autonomic Pharm slides 121-126)
(Isuprel, Dobutamine, Dopamine, Epinephrine, Norepinephrine)
342
*Practical * approaches to increase intrinsic myocardial contractility
Increase b1 receptor density
* b1 adrenergic antagonists *(review Autonomic Pharm slides 121-126)
(Metoprolol & Carvedilol)
343
Digoxin
Cardiac Glycosides
344
Digoxin
Cardiac effects
*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)*
345
Digoxin
Pharmacokinetics
*T1/2 36-48 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
346
Digoxin
| Adverse Effects
‘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*
347
Digoxin
| Role in treatment of Heart Failure
```
*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
```
348
Digoxin
| Correction of Adverse Elevations in Plasma Digoxin
* 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*
349
Phosphodiesterase 3 Inhibitors
Inamrinone & Milrinone
350
Inamrinone & Milrinone
| Cardiovascular Effects
Directly stimulate myocardial contractility
Accelerate myocardial relaxation
Balanced arterial & venous dilation
--> decrease TPR, PVR, decrease LV, RV filling pressures
all increase CO
351
Inamrinone & Milrinone
| PK & Therapeutic uses
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*
