HemeOnc module

-antimetabolites inhibit the cell cycle in the S phase, by preventing DNA synthesis

-Bone marrow suppression (worse if given IV and at high doses)
-Stomatitis (ulcers and mucositis in mouth, throat, and intestines)
-Nausea and vomiting (worse at high doses)

-cell cycle specific antimetabolite (inhibits S phase)
-inhibits thymidine synthetase, thus inhibiting thymidine synthesis and DNA replication
-can be used as a radiosensitizer

-Folinic acid
-Given with 5 FU to potentiate its cytotoxic effects by stabilizing its binding to thymidine synthetase
-Also given to counteract the toxic effects of folate antagonists

-Myelosuppression
-Mucositis
-diarrhea that can be life threatening
-can cause hand-foot syndrome (plamar and plantar rashes)
-Patients with dihydropyrimidine dehydrogenase deficiency have increased toxicity

-cell cycle specific anti-metabolite (inhibits S phase)
-Converted to 5FU systemically with increased amounts being converted in tumor cells
-5FU then inhibits thymidine synthetase and thymidine synthesis

-can be given orally, whereas 5FU can only be given IV
-not converted to 5FU until inside tissue by thymidine phosphorylase, and remains in tissues like continuous infusion

-Mucositis
-Diarhhea
-Plantar-palmar/Hand-foot syndrome (worse than 5-FU)

-emollients (i.e. moisturizers)

-Cell cycle specific antimetabolite (inhibits S phase)
-Arabinose form of cytosine that competetively inhibits DNA polymerase and incorporates into DNA

-Requires high doses and continuous infusion, because is rapdily inactivated by cytidine deaminases, especially in the CNS
-Can be given intrathecally

-Myelosuppression
-SEVERE N/V
-Allopecia
-CNS toxicity, including cerebellar
-Conjunctivitis
-Tumor lysis syndrome

-High dose boluses are associated with increased neurotoxicity
-MUST dose reduce with renal impairment, or can incurease CNS toxicity
-Vigour hydration and allopurinol administration to preven tumor lysis syndrome (increased uric acid levels)
-Antiemetics (5HT-3 antags and steroids) to prevent severe N/V
-Growth factors (G-CSF or GM-CSF) for elderly
-Steroid eyedrops can be given for conjunctivitis
-Intrathecal administration can cause seizures, peripheral neuropathy, encephalopathy, and arachnoiditis from preservatives

-cell cycle specific antimetabolite (inhibits S phase)
-closely related to ARA-C; iincorporated into DNA and inhibits DNA polymerase

-has 20x higher tissue concentrations and longer t1/2 than ARA-C

-myelosuppression
-Generalized rashes
-Flu-like symptoms
-Severe: ARDS and pulmonary edema, esp. when combined with radiation

-Treat flu-like symptoms with acetaminophen
-Rash may respond to steroids
-MUST dose-reduce for hepatic dysfunction

-5-FU (thymidine)
-Capecitabine (thymidine)
-Cytirabine (cytosine)
-Gemcitabine (cytosine)

-cell cycle specific antimetabolite (inhibits S phase)
-Inhibits pyrimidine ring biosynthesis
-Allopurinol can increase 6MP toxicity, because 6MP is metabolized by xanthine oxidase, which allopurinol inhibits

Fludarabine

-cell cycle specific antimetabolate (inhibits S phase)
-Inhibits dihydrofolate reductase, which prevents reduction of folate into its active form
-Decreased levels of reduced folate decreases thymidine synthesis, which in turn inhibits DNA synthesis

-Neurotoxicity
(most common intrathecal chemotherapy)

-Hepatoxicity

-Myelosuppression
-Mucositis

-Mucositis
-Nephrotoxicity
-Hepatotoxicity
-Requires Leucovorin rescue to prevent myelosuppression, mucositis, diarrhea, and N/V (Leucovorin will not prevent nephrotoxicity and hepatotoxicity)

-cell cycle phase-nonspecific
-contain reactive alkyl groups that covalently bond to DNA, causing ds or ss breaks in DNA
-ss and ds breaks inhibits replication and causes apoptosis

-Myelosuppression with nadir at 7-10 days (except nitrosureas have delayed myelosuppression)
-Sterility and lowered sperm count (kill germ cells)
-Secondary melignancies, with AML most common
-Allopecia
-N/V, stomatitis, diarrhea

-most versatile alkylating agent; cell cycle phase nonspecific
-Derivative of mustard gas; alkylates guanine in DNA, forming ss and ds breaks

-Hemorrhagic cystitis, caused by the active metabolite acrolein
-Myelosuppression, but platelet sparing
-total allopecia
-Delayed N/V (onset >48 hours, severe)
-Infertility
-Secondary melignancies

-alkylating agent (cell cycle phase non-specific); derivative of nitrogen mustard
-causes alkylation of guanine and ss breaks

-Hemorrhagic cystits from acrolein metabolite
-CNS toxicity

-Mesna has a thiol group that binds to acrolein metabolite of cyclophosphamide and ifosfamide and prevents hemorrhagic cystits
-Only given with high doses of cyclophosphamide
-ALWAYS given with ifosfamide

-alkylating agents that couse ds breaks in DNA (cell cycle phase non-specific)
-Have excellent CNS penetration, used for brain tumors
-Caused delayed onset and recovery of myelosuppression

-non-classic alkylating agent
(cell cycle phase non-specific)

-taken orally on empty stomach
-causes Myelosuppression
-Is an MAO inhibitor; interacts with TCAs, tyramine, meperidine, ephedrine, and amphetamines
-Disulfuram reaction with alcohol

-Alkylating agent, inhibits RNA, DNA, and protein synthesis although mechanism unclear

-Taken orally and crosses the blood brain bariier, making it the DOC for brain tumors
-High incidence of neutropenia and PCP prophylaxis is needed

-alkylating agents that form strong covalent bonds with guanine and adenine bases
-cell cycle phase nonspecific

all cause neurotoxicity, mostly peripheral neuropathy

-heavy metal compound; alkylating agent (cell cycle phase nonspecific)

-Causes SEVERE N/V; the nausea and vomiting side effects of new drugs are always tested against Cisplatin
-Nephrotoxicity: electrolyte loss, especially Mg and K, from direct damage to the tubules; must monitor kidney ffunction
-Neuropathies
-Ototoxicity
-Only causes MILD myelosuppression, so can be used in combo with radiation and myelosuppressive drugs

-structural analog of Cisplatin; heavy metal alkylating agent (cell cycle phase non-specific)

-Myelosuppression
-N/V
-Neuropathies
-Always dose based on kidney function because exclusively excreted in the urine

-heavy metal aklylating agent (cell cycle phase non-specific)

-Causes the worst neuropathies, including peripheral neuropathies that can be permanent
-50% of patients get thermal dysesthesias, where they cannot drink or eat anything cold or will get severe pain in jaw and throat
-Rash
-Mg and Ca gluconate supplementation reduces neuropathies but may compromise efficacy

-Used for colon cancer in combo with 5-FU

-vinca alkaloid "spindle poison" that prevents the assembly of microtubules
-cell cycle phase specific: inhibits mitosis phase

-vinca alkaloid "spindle poison" that prevents the assembly of microtubules
-cell cycle phase specific: inhibits mitosis phase

-vinca alkaloid "spindle poison" that prevents the assembly of microtubules
-cell cycle phase specific: inhibits mitosis phase

-FATAL IF GIVEN INTRATHECALLY
-peripheral neurotoxicity, including parasthesias and foot drop
-CNS neuropathy: jaw pain, ataxia, facial palsies
-Constipation, ileus and abdominal pain because inhibits peristalsis
-Vesicant (blistering agent if leaks out onto skin)
-Needs to be dose reduced for hepatic dysfunction (metabolized by liver)

-FATAL IF GIVEN INTRATHECALLY
-myelosuppression
-neurotoxicity
-vesicant (blistering agent)
-Needs to be dose reduced for hepatic dysfunction (metabolized by liver)

-FATAL IF GIVEN INTRATHECALLY
-myelosuppresion,
-neurotoxicity
-vesicant
-Needs to be dose reduced for hepatic dysfunction (metabolized by liver)

a.k.a. taxol
-binds to tubulin and prevents dissambly of microtubules
-cell cycle phase specific: inhibits Mitosis phase

-binds to tubulin and prevents dissambly of microtubules
-cell cycle phase specific: inhibits Mitosis phase

-Hypersensitivity reaction (the oil taxol is mixed in is immunogenic); requires premedication
-Peripheral neuropathies and neurotoxicity that can be severe
-Myelosuppression
-Mucositis
-Myalgias
-Alopecia
-dose reduce for hepatic dysfunction

-Fluid retention syndrome due to capillary leakage; must premedicate with corticosteroids to prevent peripheral and pulmonary edema
-myelosuppression
-allopecia
-dose reduces for hepatic dysfunction

Camptothecin that inhibits topoisomerase I enzyme needed for DNA repair after single strand breaks
-cell cyle phase specific: arrests G2

Camptothecin that inhibits topoisomerase I enzyme needed for DNA repair after single strand breaks
-cell cyle phase specific: arrests G2

-Severe diarrhea ("I ran to the can"); can be early or delayed; treat with loperamide
-myelosuppression

-causes PROFOUND myelosuppression; must treat the resulting neutropenia with growth factors

-Podophyllotoxin that inhibits topoisomerase II enzymes needed for DNA strand repair
-cell cycle phase specific: arreasts cells in G2

-Anthracycline
-mechanism of anthracyclines not fully understood; intercalate between DNA base pairs, bind to DNA and generate free radicals that cause breaks, directly damage DNA, inhibit RNA synthesis
-non-specific

-Both acute and chronic cardiotixicty (1% of breast cancer patients will get CHF); must establish normal heart function before use; cardiac toxicity is cumulative and must limit lifetime dose
-Severe N/V/D
-Sterility/amenorrhea
-Vesicant
-Total alopecia
-Mucositis
-Requires dose reduction for hepatic dysfunction

-Forms complex wtih DNA that creates free radicals and causes strand breakage
-cycle phase specific: arrests G2 phase

-cumulative pulmonary fibrosis
-Fevers: premedicate with acetiminophen
-Hypersensitivity reaction, esp. if have lymphoma; give test dose

-Inhibits ribonucleotide reductase, which is required for DNA subunit synthesis
-Cell cycle phase specific: arrests S phase

-myelosuppression, esp. neutropenia

-breaks down asparagine, reducing protein synthesis and nucleic acid synthesis
-normal cells and resistant tumors have high levels of asparagine synthetase, which regenerates more asparagine

-Hepatotoxicity
-Pancreatitis
-Hypersensitivity
-Cerebral dysfunction

-mainly used for hepatitis B and C
-Causes flu-like syndrome
-severe fatigue
-neurological: vertigo, confusion, depression

-monoclonal antibody against CD20 antigen expressed by melignant B cells in Non Hodgkins Lymphoma
-leads to complement lysis

-Infusion reaction and hypersensitivity: requires premedication with antihistamine
-hypotension

-monoclonal antibody against metastatic breast cancers which overexpress HER/neu 2 oncogene

-monoclonal antibody against metastatic breast cancers which overexpress HER/neu 2 oncogene

-Cardiotoxicty, especially when used with taxanes and anthracycline: must check baseline ejection fractions before and after use
-Rash
-infusion reaction

-Inhibits bcr-abl tyrosine kinase in cells with Philadelphia chromosomes
-DOC for CML

-administered orally
-metabolized by cyp3A4, with possible drug interactions

Inhibits ras activation by VEGF and EGFR tyrosine kinases, which then decreases angiogenesis and proliferation

Inhibits ras activation by VEGF and EGFR tyrosine kinases, which then decreases angiogenesis and proliferation

-can cause hypertension and hemorrhage due to their ability to limit angiogenesis

-EGFR receptor antagonist

-EGFR receptor antagonist

-acneiform rash

-inhibit cytokines; antiangiogenic, immunomodulatory, and antineoplastic
-multiple myeloma

-teratogens
-High risk of thrombosis, especially when combined with steroids: need to use with warfarin
-Peripheral neuropathy/tremors
-Steven-Johnson rash
-Bone marrow suppression

-T and B cell cancers

-monoclonal antibody that binds to VEGF and decreases angiogenesis

-Causes hypertension with proteinuria
-causes GI bleeding and perforation
(due to its limiting of angiogenesis)

GnRH analog given IM or SC every 1, 2, 3, or 4 months for the treatment of prostate cancer

GnRH analog given IM or SC every 1, 2, 3, or 4 months for the treatment of prostate cancer

-bone loss: use with bisphosphonates
-Gynecomastia
-Flare reaction
-hot flashes
-impotence/loss of libido
-mood changes

antiestrogen receptor modulators used orally once a day for breast cancer

-endometrial cancer: requires PAP smears
-eye changes: requires eye exams
-elevated liver function tests
-thromboembolism
-hot flashes
-mood changes

-Little or no bone loss
-Cancer prevention
-Increase HDL

-estrogen receptor antagonist that downregulates the receptor
-given as monthly IM injection for metastatic breast cancer

-thrombosis
-hot flashes

-aromatase inhibitors for breast cancer in postmenopausal females
-more potent than tamoxifen

-bone loss: use with bisphosphonates
-myalgias, arthralgias
-mood changes
-weight loss
-hot flashes

-anti-androgens
-Hot flashes
-Loss of libido and impotence

1. Female anophele mosquito innoculates sporozoites into human host
2. Exoerythrocytic phase: sporozoite infects hepatocytes, matures into schizont, and releases merozoites
3. Erythrocytic phase: Merozoites infect RBCs, mature into trophozoites, then schizonts which burst and release more infective merozoites
4. Some of the parasites within the erythrocytic stage mature via sexual reproduction into gametocytes, which are taken up by the anaphele female mosquito, undergo fertilization, and mature back into sporozoites
5. P. Vivax and P. Ovale have a latent exoerythrocytic stage, where they remain in hepatocytes as dormant hypnozoites that can cause relapses

-Diffuses into food vacuole of parasite
-Weak base that becomes protonated and trapped within the acid food vacuole
-Inhibits heme polymerase, the enzyme responsible for polymerizing heme into hemozoin
-The unpolymerized heme is toxic to the parasite's cells

-Attacks the organisms in the erythrocytic stage, so its use as a curative agent is limited to P. Falciparium (and P. malariae) infections
-Used as prophylaxis in areas where P. Falciparium is sensitive
-Used in acute attacks when P. Falciparium is sensitive
-Drug of choice for pregnant women with uncomplicated chloriquine sensitive malaria

-Oral usage is afer because it avoids wide swings in concentrations and side effects from high doses
-Antacids interfere with absorption

-Has a high affinity for melanin, and is taken up by tissues that have high melanin concentrations
-Retinopathies
-Depigmentation of the hair
-Pruritis
-Skin eruptions
-Partial alopecia
-Corneal opacity
-Porphoryia
-Extraocular muscle palsies

-can cause hypotension and arrhythmias (structurally similar to antiarrhythmics)

-Quinine=oral form; Qunidine=IV form
-Oral quinine must be used in combination with other drugs because is too slow acting to be effective alone
-Quinine is administered with Doxycycline, Atovaquone/Proguanil, or Clindamycin
-Antacids inhibit Quinine absorption

-IV Quinidine is used in severe cases of malaria, regardless of resistance against chloroquine
-Oral Quinine plus clindamycin is recommended for chloroquine resistant P. falcifarium in pregnant patients
-Oral Quinine plus doxycycline or plus Malranone for Chloroquin resistant P. Falciparium
-Not used for prophylaxis because continued use can be toxic

Not clear, but forms a hydrogen bonded complex with ds DNA that inhibits transcription and ultimately protein synthesis

-Quinine is an isomer of quinidine used to treat cardiac arrhythmas, and therefore can cause arrhythmias
-Hypotension
-CNS disturbances
-nausea and vomiting from irritation of the gastric mucosa

-The constellation of side effects caused by higher concentrations of Quinine:
-Nausea
-Dizziness
-Tinnitus
-Headache
-Blurred vision

-A toxic reaction associated with continued administration of Quinine, which prevents its us as a prophylactic agent
-Acute hemolytic anemia associated with renal failure, 20-50% of patients die

-Used as prophylaxis in areas with cloroquine resistant Falciparium
-Can be used as treatment against Chloroquine resistant falciparium AFTER quinine
-NOT recommended in pregnancy
-Does not act as quickly as quinine, and should not be used in severe cases of falciparium

-Administred orally
-Has half life of 13 to 33 days
-Therefore, caution should be taken if need to switch medications
-Should not be combined with other drugs that effect cardiac conduction, such as quinidine or beta blockers

-Vivid dreams and neuropsychiatric symptoms
-Vertigo
-Visual disturbances
-Insomnia
-Should not be used in patients with a history of epliepsy or psych disorders

-These agents do not work alone, but work synergystically when used together
-Pyrethamine inhibits dihydrofolate reductase (like TMP)
-Sulfadoxine inhibits dihydropteroate synthetase
-Both inhibit different steps in folate metabolism

-Primarily active against the erythrocytic stage, but may have some activity against the exoerythrocytic stage
-Used in combination with quinine

-Blood dyscrasias (granulocytopenia, thrombocytopenia, neutropenia, aplastic anemia
-Folic acid deficiency
-Steven Johnson syndrome (severe allergic reaction to sulfa)

-ONLY drug effect against the exoerythrocytic/hypnoozie stage
-Primaquine plus a drug against the erithocytic stage can cure P. vivax and ovale
-Can be used as terminal prophylaxis in people known to be exposed to P. vivax and ovale
-Contraindicated in pregnancy

-Orally
-Has t1/2 3-6 hours, so needs to be given daily

-Causes hemolytic anemia in patients with glucose 6 phosphate dehydrogenase deficiency

-Atovquone inhibits cytochrome bc1 complex (complex III) of the electron transport chian in plasmodia
-atavaquone's inhibition of complex III also inhibits electron transfer to ubiquinone, which then leads then prevents dihydroorotate dehydrogenase from producing orotate used for pyrimidine synthesis
-Proguanil in its prodrug form lowers the effective concentration at which atovaquone collapses the mitochondrial membrane potential

-Recommended for prophylaxis after mefloquine and doxycycline, because does not have the neurological side effects of mefloquine

-Use with caution in patients with severe renal impairment
-Abdominal pain, N/V, headache

chloroquine once a week for 2 weeks before, while on location, and four weeks after
PLUS
Primaquijne for 2 weeks after last exposure

Mefloquine
or doxycycline
or atovaquone/proguanil

-Chloroquine PO
-Quinidine IV if severe

-Quinine PLUS doxycycline
or PLUS doxycycline or PLUS clindamycin or PLUS pyrimethamine/sulfadiazine
-Quinidine IV for severe attack

-Primaquine

-Inhibits activation of the cerbellum by the inner ear via H1 and M receptors in response to motion
-Inhibition of the cerebellum then leads to less activation of the emetic center

-Cyclizine
-Meclizine
-Promethazine (has significant anti-D2 activity)
-Diphenhydramine

-Most of the side effects are due to their anti-muscarinic activity
-Incoordination
-Tremors
-Sedation
-Confusion
-Insomnia
-Tinnitus
-Dizziness
-Urinary retention
-Blurred vision
-Exacerbation of narrow angle glaucoma

-transdermal antimuscarinic
-used for motion sickness
-also used for post operative nausea and vomiting

antimuscarinic: dry mouth, urinary retention, blurred vision, exacerbation of narrow angle glaucoma

-Block D2 receptors in the area postrema chemoreceptor trigger zone and in the nucleus solitarius
-Inhibition of the area postrema and inhibition of the NTS results in less stimulation of the medullary emesis center

Antipsychotics:
-Prochlorperazine
-Metoclopramide

-Sedation
-Acute dystonia
-Orthostatic hypotension
-extrapyramidal symptoms

-Has anti-emetic properties: blocks D2 receptors in the chemoreceptor trigger zone and NTS
PLUS
Blocks 5HT3 receptors centrally and on vagal afferents
-Has prokinetic activity in the GI tract and enhances transit: sensitizes M receptors
-Therefore, it is used to ameliorate the nausea and vomiting that accompanies GI dysmotility syndromes

-Inhibits 5HT-3 receptors on vagal afferents, which are activated by the 5HT-3 released in the GI tract in response irritants
-Also inhibits 5HT3 receptors in the nucleus solitarius and area postrema, which reduces stimulation of the medularry emesis center in response to blood born emetics and irritants

Ondansetron

-reduce chemotherapy induced nausea
-upper adbominal irritation
-hyperemesis of pregnancy

-Constipation
-Diarrhea
-Minor ECG changes
-Light headedness and headache

-Effects of drug persist even after serum levels decrease
-Extensively metabolized by p450 enzymes
-Decrease dose in hepatic dysfunction

Oranabinol
-stimulates CB1 receptor

-High protein binding (interactions)
-sympathomimmetic activity
-paranoid reactions
-marijuana like high
-abstinence syndrome upon withdrawal

Used in cancer chemotherapy when other agents are not effective; also stimulates appetite

-Suppress peritumoral inflammation and prostaglandin production

-suppress peritumoral inflammation and prostaglandin production

-Substance P receptor antagonist
-Used as an anti-emetic because inhibits activation of vagal afferents innervating the nucleus solitarius

-Used in combo with other therapies for delayed nausea
-Highly bound to plasma proteins and avidly metabolized by cyp450
-Dosage adjustment required for liver dysfunction and for drugs like dexamethasone that are also metabolized by cyp450

-Metocloperamide or Prochloroperazine (antipsychotics, D2 antagonists)
-5HT3 antagonists

-Promethazine
-5HT3 antagonists
(Ginger and vitamin B6 have been shown to reduce nausea in pregnant women)

-D2 antagonists
-5HT3 antagonists

-Propofol

-Pre treatment: 5-Ht3 antagonists, dexamethasone, Aprepitant
-Post treatment: Aprepitant
(for chemo with low risk of N/V, dexamethasone administered prior to therapy can be used alone)