Pharmacology of Chemotherapy Flashcards

This is a pharmacology review of chemotherapy.

Examples of Nitrogen Mustards (Alkylating Agents)

Bendamustine, chlorambucil, cyclophosphamide, ifosfamide, melphalan, mechlorethamine

Examples of Nitrosoureas (Alkylating Agents)

Carmustine, lomustine, streptozocin

Examples of Other Alkylating Agents

Busulfan, dacarbazine, lurbinectedin, procarbazine, temozolomide, thiotepa, trabectedin

How do alkylating agents work?

They alkylate by covalently binding reactive groups with nucleophilic groups of proteins and nucleic acids, causing cross-linking of DNA

Mechanisms of resistance to alkylating agents

Decreased uptake, activation of antiapoptotic pathways, increased drug inactivation, increase in DNA repair enzyme expression

Important administration consideration for oral chlorambucil

Administer on empty stomach because food reduces absorption

Important administration consideration for oral procarbazine

Drug interacts with MAOIs, TCAs, SSRIs, and other drugs because its metabolite is a weak MAOI; Drug has disulfiram-like reaction with alcohol

Black box warnings for carmustine

Myelosuppression, pulmonary toxicity

Black box warnings for ifosfamide

Myelosuppression, hemorrhagic cystitis, nephrotoxicity

Key counseling for high-dose busulfan regimens

Seizure prophylaxis (phenytoin, benzodiazepine, levetiracetam)

How to prevent hemorrhagic cystitis with cyclophosphamide and ifosfamide

Coadministration of mesna is necessary with high-dose cyclophosphamide and ifosfamide

Risk factors for ifosfamide-induced encephalopathy

Renal dysfunction, hypoalbuminemia; potential risk factor for concomitant CYP3A4 inhibitors, such as aprepitant

List the Platinating Agents

Carboplatin, Cisplatin, Oxaliplatin

Mechanism of action of platinating agents

Form intrastrand and interstrand crosslinks, which inhibit DNA synthesis

Resistance mechanisms to platinating agents

Repair of DNA damage, reduced uptake into cells, or inactivation by intracellular glutathione

Administration specification of platinating agents intravenous administration

Avoid aluminum needles or administration sets because of reaction and loss of potency

Administration consideration for oxaliplatin

Flush line with dextrose 5% in water before and after infusion; Do not prepare with any chloride-containing solution

When is desensitization indicated?

May be indicated to continue treatment after occurrence of anaphylaxis, which is thought to be immunoglobulin E (IgE) mediated for platinum agents

Platinating agents that require renal adjustment

Carboplatin, cisplatin, oxaliplatin

Platinating agent that undergoes nonenzymatic metabolism and is renally cleared

Cisplatin

Relevant CYP interaction consideration for oxaliplatin

Substrate of OCT2

Black Box Warnings for Carboplatin

Myelosuppression, vomiting, hypersensitivity reactions

Black Box Warnings for Cisplatin

Myelosuppression, nausea and vomiting, nephrotoxicity, peripheral neuropathy

Key counseling points for carboplatin

Use Calvert formula for dosage calculation

Key Counseling points cisplatin

Pretreatment hydration and maintenance of adequate urinary output are needed; Highly emetogenic, four-drug prophylaxis is recommended

Chemoprotectant, may be used to prevent cisplatin nephrotoxicity and neutropenia

Amifostine

Key counseling points oxaliplatin

Avoid exposure to cold, including beverages with ice

Pyrimidine analogs (antimetabolites)

5-fluorouracil, capecitabine

Cytidine analogs (antimetabolites)

cytarabine, gemcitabine

Purine analogs (antimetabolites)

clofarabine, cladribine, fludarabine, nelarabine, pentostatin, mercaptopurine, thioguanine

Mechanisms of action (antimetabolites)

Structural analogs of nucleotide bases disrupt production of nucleic acids; All agents inhibit DNA synthesis

Administration considerations capecitabine

Capecitabine is a prodrug of fluorouracil with about 80% bioavailability; Administer orally in two divided doses

Administration considerations mercaptopurine

Oral form should be taken on an empty stomach

Administration considerations mercaptopurine and drug interactions

Avoid concomitant allopurinol, which inhibits xanthine oxidase; Deficiency in TPMT or NUDT15 enzyme results in increased levels of mercaptopurine

Administration considerations for intravenous cladribine

Cladribine: intermittent or continuous infusion

Antidotes for antimetabolites

Uridine triacetate may aid in recovery after fluorouracil/capecitabine overdose or toxicity

Metabolism of capecitabine

Extensive liver metabolism with subsequent activation to fluorouracil via hydrolysis by thymidine phosphorylase within cells

Main CYP interaction of note for clofarabine

Substrate of OAT1/3, OCT1, and OCT2

Black box warning cytarabine

drug toxicities, mainly myelosuppression

Black box warning fludarabine

myelosuppression, neurotoxicity, autoimmune effects

Key toxicities for capecitabine

diarrhea; Hand–foot syndrome; Myelosuppression (less)

Presentation: corneal toxicity, conjunctivitis; prophylaxis with steroid eye drops 4 times a day and for 24 hours after last dose

high-dose cytarabine (HiDAC)

Treatment parameters toxicity management capecitabine: Withhold treatment until…

diarrhea resolves to at least grade 1

List the Folate Antagonists

methotrexate (MTX), pemetrexed, pralatrexate

Mechanisms of action (folate antagonists)

Antifolates lead to cessation of DNA synthesis; S phase specific

MOA methotrexate

Binds dihydrofolate reductase (DHFR) to inhibit formation of reduced folates

Resistance mechanisms (folate antagonists)

Reduced transport into cells via the reduced folate carrier, reduced polyglutamation, altered target or binding to target, expression of multidrug resistance transporters

Mtabolism: Methotrexate

converted by hepatic aldehyde oxidase, then polyglutamates are created intracellularly

Methotrexate elimination

Reduced in renal or hepatic impairment and in those with fluid accumulation; risk delayed clearance and increased risk toxicities

HD-MTX: Requires leucovorin rescue

Leucovorin is reduced folate, which allows DNA synthesis in the presence of MTX

Requires urinary alkalinization

IV or PO sodium bicarbonate; sodium acetate is alternative

List the Anthracyclines

daunorubicin, doxorubicin, liposomal doxorubicin, idarubicin, epirubicin, mitoxantrone

The mechanisms of action for Anthracyclines

Induce apoptosis from DNA damage and inhibition of topoisomerase II, free radical formation, altered signal transduction

Resistance mechanisms to anthracyclines

Efflux out of cell via multidrug resistance (MDR) pumps, reduced activity of topoisomerase II, overexpressed BCL-2

Anthracyclines: List the life time maximum dose

doxorubicin up to 500 mg/m2, daunorubicin up to 550 mg/m2, epirubicin up to 900 mg/m2, idarubicin up to 150 mg/m2

Toxicity management cardiotoxicity for anthracyclines

Assess ejection fraction (EF) before treatment

Anthracyclines related cardiotoxicity acute toxicity

Arrhythmia, conduction abnormalities, pericarditis, myocarditis

Epipodophyllotoxins, Topoisomerase II Inhibitors:

Etoposide (VP-16), and teniposide

Mechansim of action: Topoisomerase II Inhibitors

Inhibition of topoisomerase II, which stabilizes the DNA cleavage complex, leading to DNA strand breaks

Administration considerations: Etoposide

Concentration must be less than 0.4 mg/mL; may administer undiluted

Etoposide hypersensitivity reactions

Signs and symptoms can include fever, chills, flushing, bronchospasm, dyspnea, tachycardia

Counsel patients taking Topoisomerase II Inhibitors

Signs and symptoms hypersensitivity reaction; secondary malignancy risk

Agents that are Topoisomerase I Inhibitors

irinotecan, topotecan

Mechanisms of action for Topoisomerase I Inhibitors

inhibition of topoisomerase I via formation of stable cleavable complexes, which interferes with DNA replication

Relevant CYP interactions considerations: Irinotecan

substrate of BCRP/ABCG2, P-glycoprotein/ABCB1, UGT1A1, OATP1B1/1B3 (SLCO1B1/1B3), CYP3A4

Administration for patients taking irinotecan

Usual treatment parameters: ANC at least 1,500 cells/mm3, PLT at least 100,000 cells/mm3, resolved diarrhea

Toxicity Management: Irinotecan and Diarrhea

Acute: Usually within 1 hour of completion

Delayed diarrhea More common with every-3-week regimen than weekly lower-dose regimens

More than 24 hours after chemotherapy

Toxicity Management: Irinotecan and diarrea; acute

Atropine 0.25–1 mg IV or subcutaneously

List agents of taxanes

Cabazitaxel, docetaxel, paclitaxel, albumin-bound paclitaxel\

Mechanism of action: Taxanes

Microtubule inhibitor: bind polymerized tubulin along length of microtubule to enhance polymerization.

Resistance mechanisms for taxanes

Altered tubulin or tubulin binding site, overexpression of P-glycoprotein efflux pump

Docetaxel: contraindications

Alcohol, Patient counseling for fluid retention

Vinca agent names

Vinblastine, vincristine, vinorelbine

Vinca mechanisms of action

Binds tubulin, inhibits tubulin polymerization stopping division

Black box warnings: Vinblastine

Extravasation, IV use only

Classes of Vinca agents

General class toxicities: Constipation, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, jaw pain; vesicants

Agents which are Epothilones and Halichondrins

Ixabepilone (epothilone B analog), eribulin (halichondrin analog)

Mechanisms of action for Epothilones and Halichondrins

Ixabepilone binds β tubulin subunits to inhibit microtubule dynamics by promoting tubulin polymerization, eribulin inhibits microtubule function by binding β tubulin to block G2-M phase

Resistance mechanisms for Epothilones and Halichondrins

Ixabepilone is not affected by overexpression of P-glycoprotein pumps or tubulin mutations, eribulin is not affected much by P-glycoprotein efflux pump

Administration considerations: Ixabepilone

Must be reconstituted with diluent provided by manufacturer

Ixabepilone: Key Dosing

1. Dosing of 40 mg/m2 IV over 3 hours every 3 weeks; dosage cap at 2.2 m2 (88 mg)

Eribulin: Key Dosing

1.4 mg/m2 on days 1 and 8 of 21-day cycle infused over 2–5 minutes

Which are histone deacetylase inhibitors

Belinostat, panobinostat, romidepsin, vorinostat

Classes of histone deacetylase inhibitors

Epigenetic modifiers

what to monitor for belinostat infusion

Hepatotoxicity

Long term risks for differentiation agents

Carcinogenic

Long term risks for arsenic trioxide

Electrolytes, Encephalopathy, Prolonged QT interval

Arsenic trioxide: Monitoring and toxicity management

Fever, volume level, respiratory status

All trans retinoic acid : monitoring and potential treatment

Assess coagulation at baseline before treatment on ATRA

Vesanoid delivery

Administer sublingually by squeezing contents under the tongue

Agent derived from asparagine enzymes

escherichia coli

Time sensitive administration following TDM

72 hours

Important risks for administering asparagase enzymes

Thrombotic events

Routes of administration for asparaginase

IV,SC,IM,IA

Resistance pathways for efflux of chemotherapy agents

P-glycoprotein

Important adverse effects to monitor in cytotoxic chemotherapy

Urine retention, blood sugar increasing

Topical interventions following extravasation

Dexrazoxane, DMSO, THIO