_Cisplatin:_ 1. Dose Limiting Toxicities 2. Prevention:

_Cisplatin:_ Dose Limiting Toxicities Nephropathy: cumulative! dose-limiting Early signs = potassium and magneisum wasting and decrease GFR To Prevent: Hydration Supplemental electrolytes May be on furosemide and/or mannitol to prevent

Chemo Flashcards by Kate T

Alkylating Agents

Nitrogen Mustards (Cyclophosphamide/Cytoxan)

Nitrosureas (Carmustine)

Platinum Compounds (Cisplatin/Carboplatin)

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Alkylating Platinum Compounds:

MOA:

Alkylating Platinum Compounds:

MOA: Do not have an alkyl group, cross link guanine bases in DNA with different structural elements (platinum atom, two amines, two chlorides)

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Alkylating Agents

toxicities:

Alkylating Agents

toxicities:

Bone Marrow Suppression

biggest concern
neutropenia, hemolytic aneima, thrombocytopenia

Mucositis
* worry with airway manipulation/instrumentation

3. Skeletal Muscle Weakness

4. Seizures

5. Pneumonitis & Pulm. Fibrosis

1% fibrosis c cyclophosphamide
20-30% carmustine

6. SIADH

7. Uric Acid Nephropathy

8. Impaired Pseudocholinesterase

concern with succinylcholine

9. Nephropathy -> CISPLATIN

10. Peripheral Neuropathy -> Oxaliplatin

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Carmustine Toxicity

Pulmonary Toxicity = 20-30%

Mortality = 24-90% similar to bleomycin

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Impaired Psuedocholinesterase with alkylating agents

Can last 2-3 weeks!

Affects succinylcholine, mivacurium, esmolol, remifentanil

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Cisplatin:

Dose Limiting Toxicities
Prevention:

Cisplatin:

Dose Limiting Toxicities

Nephropathy:

cumulative!
dose-limiting
Early signs = potassium and magneisum wasting and decrease GFR

To Prevent:

Hydration
Supplemental electrolytes
May be on furosemide and/or mannitol to prevent

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Oxiplatin

Dose Limiting Toxicities:

Oxiplatin

Dose Limiting Toxicities:

Peripheral Neuropathy

Dose-limiting effect.
Presents as tingleing around mouth, fingers, toes.
Avoid cold contact.

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Anti-Metabolite Agents

Methotrexate (Folic Acid)

Fluorouracil (Pyrimidine)

Mercaptopurine (Purine)

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Methotrexate

MOA:

Methotrexate:

MOA: Binds to dihydrofolate reductase, prevents reduction of FH2 to FH2 and prevent synthesis of DNA nucleotides.

Normal pathway of Folate:

Folate -> FH2 -> FH4 by enzyme: dihydrofolate reductase.

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Methotrexate

Toxicities

Methotrexate

Toxicities

1. Fulminant pumlonary fibrosis,

non cardiogenic pulmonary edema
8%

2. Neutropenia & Thrombocytopenia

3. Mucositis & GI ulceration

4. Renal Toxicity (10%)

usually permanent

5. Hepatic Toxicity

can be reversible

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Fluorouracil

MOA:

Fluorouracil

MOA:

Inhibits thymidilate synthesase. Which inhibits nucleotide production ->

end result: inhibits DNA synthesis

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Fluorouracil

Toxicities:

Fluorouracil

Toxicities:

1. Increased risk for MI for 1 week after administration

delay surgery if possible
2. Myelosuppresion
leukopenia, thrombocytopenia, anemia
3. Alopecia
4. Neurological Defects
Ataxia - cerebellum
5. GI toxicity
d/c if stomatitis, mucositis, diarrhea
Patients at risk for GI ulceration and perforation

Hand-and-Foot Syndrome
* tingling, redness, burning, flaking, swelling, blistering of palms and toes

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Topoisomerase Inhibitor Agents

Anthracyclines: Doxorubicin, Daunorubicin

Non-anthracyclines: Bleomycin

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Topoisomerase Inhibitors - Anthracyclines

MOA:

Topoisomerase Inhibitors - Anthracyclines

MOA:

Anthracyclines; Doxorubicin, Daunorubicin:

Inhibtion of topoisomerase I and II and intercalation with DNA -> double strand DNA breaks and inhibtion of DNA & RNA synthesis (inhibtion of DNA replication)

Toposiomerase II: relaxes the DNA supercoil and breaks the strand for replication, also crticial to putting the DNA bakc together

-> If you can’t unwind the coil, you can’t replicate the DNA

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Topoisomerase Inhibitors - Non-Anthracyclines

MOA:

Topoisomerase Inhibitors - Non-Anthracyclines

MOA:

Non-Anthracyclines: Bleomycin

Topoisomerase inhibtion + binds to DNA and chelates iron leading to formation of free radicals that cause single and double strand DNA breaks

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Bleomycin

Toxicities

Bleomycin

Toxicities

Pulmonary Toxicity

(4% -> 1% = “life threatening”)
Mechanism: lungs take up high concentrations of drug and lack the enzyme hydrolase to inactivate the bleomycin
Increased risk with:
- cumulative dosing
- age
- chest radiation
- pulmonary co-morbidities
- oxygen exposure
- other chemotherapy drugs
- genetics

May progress from pulmonary fibrosis -> severe fibrosis -> death.

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Special Considerations for mangaing SE of bleomycin:

Pulmonary Toxicity:

Discontinue at first signs of toxicity: dry cough, dyspnea, tachypnea, infiltrates on CXR
Keep FIO2 concentations at or below 30% during anesthesia if possible.
1. Titrate SaO₂ ~ 90%
2. Avoiding hyperoxia = avoiding further injury from free radicals
Pre-Op: baseline serial PFTs, CXR, ABG,

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Chemotherapy agents that DO NOT cause myelosuppresion

Bleomycin

(“very little” = vincristine)

Tubulin-Binding Drugs

MOA:

Tubulin-Binding Drugs

MOA:

Binds to tubulin (microtubule dimers) to block microtubule assembly (preventing polymerization of dimers) -> cell division is arrested during metaphase -> signal for apoptosis

Tubulin-Binding Agents:

Tubulin-Binding Agents:

Vinca Alkyloids
- Vincristine
- Vinblastine
- Vinorelbine
Taxnanes:
- Paclitaxel
- Docetaxel

Vincristine

Class:

Toxicities:

Vincristine

Class: Tubulin-Binding Drug: Vinca-Alkaloid

Toxicities:

1. Peripheral Neuropathy (~100%)
1. Hyponatremia (SIADH)
1. Some autonomic neuropathy -> reversible?
4. Very little bone marrow suppression
5. Autonomic dysfunction

Myelosuppresion among vinca alkyloids

Vincristine: very little bone marrow suppression

Vinblastine/Vinorelbine: bone marrow suppression

Paclitaxel, Docetaxel

Class:

Toxicities:

Taxanes

Class: Tubulin-Binding Agents - Taxanes

Toxicities:

Peripheral Neuropathy (especially hands and feet)
Muscle & Joint Pain
Hypersensitivity Reactions: 25-30%
Cardiac:
- Bradycardia,
- HB,
- MI
Myelosuppresion
- Neutropenia devels in almost all patients
- 1% have a sepsis related death
- 11% have sepsis related death if there is concurrent liver failure

Signal Transduciton Modulating Agents:

Anti-Hormone Drugs
- Tamoxifen
- Flutamine
Aromatase Inhibitors
Monoclonal Antibodies
- Bevacizumab

_Signal Transduction Modulators_ ## Footnote **MOA:**

* Disrupt abberant growth factor: Receptor interactions in cancerous cells that prevents the intracellular signalling that would lead to cellular proliferation and survival **OR** * Target mutated receptors that give a signal to proliferate without any growth factor bound

Tamoxifen acts as

* an estrogen ***ANT-agonist*** in certain cells: breast, ovarian * and an estrogen **agonist** in other cells (uterus, liver, bone)

Flutamine acts as:

an **androgen-antagonist**, competitvely antagonizes testosterone and DHT

Tamoxifen SE:

related to **_estrogen-AGONIST_** activity * DVT * Endometrial CA * Menopausal symptoms * increased bone density (good) * improves serum cholesterol panel (good)

Flutamine SE:

r/t to **_androgen antagonis_**t effects: * gynecomastia * hot flahses * muscle weakness * **osteoporosis** * **methemoglobinemia**

MOA: Aromatase Inhibitors

Aromatase = enzyme complex that usually converts androgens into estrone in fatty tissues (breast) **MOA Aromatase Inhibitors:** Blocks actions of aromatase, blocks conversion of androgens into estrone -\> decreases level of estrone in some post-menopausal women with breast cancer

_Bevacizumab_ ## Footnote **MOA:**

Bevacizumab is a monoclonal antibody (signal transuduction modulator) **MOA:** Blocks angiogensis by inhibiting vascular endothelial growth factor [VEGF]. Works for a limited amount of time and then cancer is able to adapt. :(

Bevacizumab SE:

Hypertension with monoclonal antibodies = 35-45%

Complete Response:

Complete dissapearance of all cancer without evidence of new disease ***for at least 1 month***

Partial Response

50% reduction in tumor size or other objective markers.

Stable Disease:

A patient whose tumor size neither grows nor shrinks by more than 25%

Progression

25% increase in tumor size or development of new lesions ***while on treatment.***

Most Common Drugs to cause problematic extravasation: (classes)

Anthracyclines Vinca Alkaloids Taxanes

_Alkylating Agents_ ## Footnote **MOA:**

_Alkylating Agents_ ## Footnote **MOA:** Reactive alkyl groups form covalent bonds with nucleotide bases in DNA, RNA "Cross-linkes guanine on the DNA helix, thereby making DNA stuck in coil. If it cannot uncoil, it cannot replicate."

To prevent methotrexate nephrotoxicity:

Alkalinize urine and **hydrate!** Renal toxicit is usually *permanent.*

In case of GI upset r/t methotrexate and 5FU

perforation is possible (more so for 5FU) and would be complicated by thrombocytopenia.

Hydroxyl Free Radicals with Anthracyclines

Free radical production is greately stimulated by the interaction of doxorubicin with iron (blood)

_Anthracycline_ ## Footnote **Toxicities:**

_Anthracycline_ **Toxicities:** Doxorubicin/Daunorubicin 1. _Substanial Bone Marrow Suppression_ * Anemia, thrombocytopenia, low WBC 70% of patients 2. _Red/Orange Urine/Sweat_ 3. **_Cardiotoxicity_** * May be more sensitive to cardiac depressive side effects of anestheticis *even if normal resting echo.* * Cumulative

_Cardiotoxicity of Anthracyclines_ Acute vs Chronic

Caused by free radical production. **Acute: 10% -\> Transient and Rare** * Tachycardia * Arrthymias * ECG chagnes and *acute ECF reduction* * Usually lasts 1-2 months **Chronic: 2% with 60% fatality** * Severe cardiomyopathy/CHF * Related to cumulative dose * Protective Therapies * Dexrazone: prevents free radical formation * **ACE-Inhibitors**

Bleomycin in lymphoma patients

_High risk for hypersensitivity._ ## Footnote Can cause fever, chills, confusion, hypotension, wheezing. **Test dose is reccomended** for lymphona patients before standard doses.