Pharmacodynamics of Antineoplastic Drugs
Session 13: Pharmacodynamics of Antineoplastic Drugs
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of Antineoplastic Drugs
Describe drug interactions associated with Antineoplastic Drugs
Describe side effects of Antineoplastic Drugs
Describe contraindications of Antineoplastic Drugs
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD projector
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Antineoplastic Drugs
Mechanism of Action of Antineoplastic Drugs
2
2
45 minutes
45 minutes
Buzzing
Mechanism of Action of Antineoplastic Drugs
Mechanism of Action of Antineoplastic Drugs
Buzzing
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With
Drug Interactions Associated With
3
3
20 minutes
20 minutes
brainstorming
Antineoplastic Drugs
Antineoplastic Drugs
brainstorming
Antineoplastic Drugs
Antineoplastic Drugs
4
4
20 minutes
20 minutes
Presentation
Side Effects of Antineoplastic Drugs
Side Effects of Antineoplastic Drugs
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Antineoplastic Drugs
Contraindications of Antineoplastic Drugs
5
5
20 minutes
20 minutes
Brainstorming
Contraindications of Antineoplastic Drugs
Contraindications of Antineoplastic Drugs
Brainstorming
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 105 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning objectives and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Antineoplastic Drugs (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
How do Antineoplastic Drugs produce their pharmacological effects?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
Alkylating Agents
In general, Alkylating agents are particularly effective when cells are dividing rapidly, but are not phase-specific.
They combine with DNA and thus damage malignant and dividing normal cells.
If a tumour is sensitive to one alkylating agent, it is usually sensitive to another, but cross-resistance does not necessarily occur.
The alkylating agents transfer alkyl (chemical) groups to DNA. DNA alkylation in the nucleus leads to the death of the cell.
Once in the cell, the alkylating agents undergo a structural rearrangement that results in the formation of an unstable intermediate, an ethylene immonium ion.
This ion either directly, or via another intermediate, a carbonium ion, transfers alkyl groups to nucleic acids such as guanine or to other cellular constituents.
Alkylation of guanine or other bases results in abnormal base pairing as well as the excision of these bases, which in turn leads to strand breakage.
The connection between DNA alkylation and death of the cancer cell has not been established; however, one of the likely mechanisms is damage to DNA that is sufficient to activate proapoptotic proteins such as p53, leading to cell death.
Mustine (Mechlorethamine)
Mustine forms highly reactive ethyleneimine ions that alkylate and cross-link guanine bases in DNA and alkylate other macromolecules, including proteins.
PST 05104 Pharmacology & Therapeutics 106 NTA Level 5 Semester 1 Facilitator Guide
Cyclophosphamide
It is an inactive prodrug given orally or intravenously.
Nitrosoureas:
Carmustine, lomustine, semustine, bendamustine
Nitrosoureas have an additional mechanism of action.
Nitrosoureas undergo another reaction, referred to as carbamoylation, with lysine residues of proteins.
The product of this reaction is referred to as a carbamoylated protein, and this process appears to limit the ability of the cancer cell to repair DNA.
This unique mechanism of action limits cross-resistance between nitrosoureas and other members of this class.
Procarbazine
It is an inactive prodrug given orally or intravenously
Platinum compounds
Cisplatin, Carboplatin etc
o Platinum compound cytotoxicity results from selective inhibition of tumour DNA synthesis by the formation of intra- and inter-strand cross-links at guanine residues in the nucleic acid backbone.
o This unwinds and shortens the DNA helix.
Antifolate analogues antimetabolites
Methotrexate
o Folic acid is required in the synthesis of thymidylate (a pyrimidine) and of purine nucleotides and thus for DNA synthesis.
o Methotrexate is a very slowly reversible competitive inhibitor of dihydrofolate reductase (DHFR).
o The affinity of DHFR for methotrexate is 100 000 times greater than that for dihydrofolate.
o Thus, methotrexate prevents nucleic acid synthesis and causes cell death. Folinic acid circumvents this biosynthetic block and thus non-competitively antagonizes the effect of methotrexate.
Pyrimidine antimetabolites
5-Fluorouracil
o 5-Fluorouracil is a prodrug that is activated by anabolic phosphorylation to form: 5-fluorouridine monophosphate, which is incorporated into RNA, inhibiting its function and its polyadenylation.
o The anabolic phosphorylation also forms 5-fluorodeoxyuridylate, which binds strongly to thymidylate synthetase and inhibits DNA synthesis.
PST 05104 Pharmacology & Therapeutics 107 NTA Level 5 Semester 1 Facilitator Guide
Incorporation of 5-fluorouracil itself into DNA causes mismatching and faulty mRNA transcripts.
Purine antimetabolites
6-Mercaptopurine (6-MP)
o 6-MP requires transformation by intracellular enzymes to 6-thioguanine which inhibits purine synthesis.
Cytotoxic Antibiotics (Anthracyclines )
Doxorubicin
o Cytotoxic actions of anthracyclines lead to apoptosis through intercalation between adjacent base pairs in DNA, leading, to fragmentation of DNA and inhibition of DNA repair, enhanced by DNA topoisomerase II inhibition.
Camptothecins (Topoisomerase I inhibitors)
o Camptothecins act during the S-phase of the cell cycle. DNA topoisomerase I is necessary for unwinding DNA for replication and RNA transcription.
o Camptothecins stabilize the DNA topoisomerase I–DNA complex. Cell killing is most likely via induction of apoptosis (programmed cell death).
Etoposide and Teniposide (Topoisomerase II inhibitors)
o DNA topoisomerase II is a nuclear enzyme that binds to and cleaves both strands of DNA.
o It is necessary for DNA replication and RNA transcription.
o Etoposide stabilizes the topoisomerase II–DNA complex, leading to apoptosis, as for camptotecins.
Vincristine and Vinblastine (Vinca alkaloids)
o Vinca alkaloids bind to β-tubulin, a protein that forms the microtubules which are essential for the formation of the mitotic spindle.
o They prevent β-tubulin polymerizing with α-tubulin and thus inhibit mitosis. Blockade of microtubular function involved in neuronal growth and axonal transport probably accounts for their neurotoxicity.
Paclitaxel (Taxanes)
o Paclitaxel binds to the β-subunit of tubulin and antagonizes the depolymerization of microtubules, halting mitosis. Cells are blocked in the G2/M phase of the cell cycle and undergo apoptosis.
PST 05104 Pharmacology & Therapeutics 108 NTA Level 5 Semester 1 Facilitator Guide
STEP 3: Drug Interactions Associated with Antineoplastic Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with Antineoplastic drugs?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below Alkylating Agents
Procarbazine
o Procarbazine blocks aldehyde dehydrogenase and consequently causes flushing and tachycardia if ethanol is taken concomitantly.
o Itis also a weak monoamine oxidase inhibitor and may precipitate a hypertensive crisis with tyramine-containing foods
Platinum compounds
Cisplatin
o Additive nephrotoxicity and ototoxicity occurs with aminoglycosides or amphotericin.
Antifolate analogues antimetabolites
Methotrexate
o Probenecid, sulphonamides, salicylates and other NSAIDs increase methotrexate toxicity by competing for renal tubular secretion, while simultaneously displacing it from plasma albumin.
o Other weak acids including furosemide and high-dose vitamin C compete for renal secretion.
o Gentamicin and cisplatin increase the toxicity of methotrexate by compromising renal excretion.
Purine antimetabolites
6-Mercaptopurine (6-MP)
o Allopurinol inhibits xanthine oxidase.
o The usual dose of 6-MP should be reduced by 75% to avoid toxicity in patients who are concurrently taking allopurinol.
o This is important because allopurinol pre-treatment is used to reduce the risk of acute uric acid nephropathy due to rapid tumour lysis syndrome in patients with leukaemia.
PST 05104 Pharmacology & Therapeutics 109 NTA Level 5 Semester 1 Facilitator Guide
STEP 4: Side Effects of Antineoplastic Drugs (20 minutes)
Alkylating Agents
Cyclophosphamide and others.
o Nausea, vomiting: These are common side effects with cytotoxic agents, which tend to target rapidly dividing cells, including those of the GI tract.
o Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles. This effect is seen most often with cyclophosphamide.
o Serious Myelosuppression: Typical of cytotoxic agents, alkylators tend to target cells that are actively dividing, such as those found in the bone marrow.
o Pulmonary toxicity (nitrosoureas and busulfan): Interstitial lung disease may occur. o Nephrotoxicity is seen most often with cyclophosphamide and ifosfamide.
o Bladder toxicity is seen most often with cyclophosphamide and ifosfamide.
o Haemorrhagic cystitis (cyclophosphamide and ifosfamide) is caused by acrolein, a metabolite of cyclophosphamide and ifosfamide. This effect can be managed by increasing fluid intake and by administering sulfhydryl donors such as N-acetylcysteine or mesna (an antioxidant). These agents bind with acrolein and form a nontoxic compound.
o Leukemia (rare): The alkylating agents work by damaging DNA. If they damage DNA in healthy cells, this may lead to mutations in the genome that rarely result in development of malignancies, particularly leukemia.
Anthracyclines:
Doxorubicin etc
o Cytotoxic actions of anthracyclines lead to apoptosis through membrane binding alters membrane function and contributes to cardiotoxicity
o Free-radical formation from anthracyclines also causes cardiotoxicity.
o Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles. The hair loss is reversible.
o Mucositis or stomatitis is an inflammatory condition of the mouth.
Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells,
such as those in the oral mucosa.
Soft tissue necrosis: If the anthracyclines become extravascular, they can damage surrounding tissue.
Infusions should be carried out slowly to reduce the risk of extravasation.
Cardiotoxicity: The free radicals generated by the anthracyclines cause peroxidation of the cardiac sarcoplasmic reticulum, leading to a Ca2+-dependent cardiac necrosis.
The reason this toxicity is selective for cardiac tissue is that catalase, able to neutralize these free radicals, is not found in cardiac tissue.
Myelosuppression: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those of the bone marrow. The bone marrow suppression is reversible but does predispose the patient to major complications such as infection while receiving treatment.
PST 05104 Pharmacology & Therapeutics 110 NTA Level 5 Semester 1 Facilitator Guide
Antimetabolites:
Methotrexate and others
o Myelosuppression: Conventional chemotherapy agents work by targeting rapidly dividing cells.
o This nonspecific effect can also target rapidly dividing cells in other areas of the body, including bone marrow and the GI tract.
o Alopecia: Cytotoxic chemotherapy agents tend to target tissues with rapidly dividing cells, such as those in hair follicles.
o Defective oogenesis or spermatogenesis results from targeting of rapidly dividing cells.
o Hepatotoxicity: Reversible elevations in liver enzymes may develop.
STEP 5: Contraindications of Antineoplastic Drugs (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the contraindications of Antineoplastic Drugs? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Alkylating Agents
Cyclophosphamide:
o Severe leukopenia, thrombocytopenia will be exacerbated (see side effects).
o Pregnancy: Like other cytotoxic agents, cyclophosphamide can cause fetal harm.
o Lactation: Cyclophosphamide is excreted in breast milk, so breastfeeding should be avoided.
Melphalan, Chlorambucil:
o Radiation: should not be administered with radiation therapy or within 4 weeks of radiation therapy (chlorambucil).
o Radiation also damages DNA and may impair DNA repair mechanisms in healthy cells, leaving them more susceptible to the DNA-damaging effects of alkylating agents.
Lomustine:
o Severe leukopenia and/or thrombocytopenia is a contraindication.
o Lactation: It is not known whether lomustine is excreted in breast milk, but breastfeeding is not advised during treatment
Antifolate analogues antimetabolites
Methotrexate
PST 05104 Pharmacology & Therapeutics 111 NTA Level 5 Semester 1 Facilitator Guide
Pregnancy: Most of the antimetabolites are teratogenic in animals.
Anthracyclines
Doxorubicin and others
o Severe cardiac disease: Anthracyclines should be used only with extreme caution and after a careful risk-benefit assessment in these patients. See Side Effects.
o Lactation: Patients should not breastfeed while using these agents.
STEP 6: Key Points (5 minutes)
Combination therapy is better than single drug therapy because there is improved cell cytotoxicity; heterogeneous tumour cell populations are killed and it reduces the development of resistance.
Anticancer drugs have serious adverse effects
Cytotoxic drugs are not totally selective in their toxicity to cancer cells.
STEP 7: Evaluation (5 minutes)
What are the indications of cyclophosphamide?
What are the general/common adverse effects of anticancer drugs?
How do Vinca alkaloids produce their pharmacological effects?
PST 05104 Pharmacology & Therapeutics 112 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 113 NTA Level 5 Semester 1 Facilitator Guide
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