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Pharmacology Hematology and Oncology (UWORLD)

Terms in this set (43)

answer: Bone marrow supression
The cell cycle consists of 4 distinct phases: G1, S, G2 and M; progression through the phases is controlled by surveillance systems (checkpoints) that interrupt the cell cycle and/or induce apoptosis if cells do not meet requirements to proceed forward:
-Transition from G1 to S (initiation of DNA replication) is controlled by a combination of cell size and nutrient status, exposure to growth factors, and proper surveillance and repair of damaged DNA
-G2 to M transition, cell again checks for DNA damage and repairs replication errors before they can be passed on to daughter cells during mitosis (additional spindle checkpoint ensures that duplicated chromosomes separate appropriately during cell division)
Cyclin-dependent kinases (CDKs) 4 and 6 control cell cycle progression from G1 to S; these CDKs are activated by cyclin D and subsequently inhibit the retinoblastoma tumor suppressor protein, leading to upregulation of transcriptional factors that progress the cell cycle to S phase (cancers exploit this; upregulation of cyclin D or inactivating mutations to retinoblastoma gene)
CDK4/6 inhibitors (e.g., Palbociclib) can be used to block cyclin D binding site on CDK, which results in decreased CDK 4/6 activation, increased activity of Rb tumor suppressor protein, and cell cycle arrest
Generally well tolerated, they often inhibit cellular replication in other rapidly dividing cells, particularly hematologic cells in the bone marrow (neutropenia, anemia, leukopenia)
option B= anthracyclines (e.g., doxorubicin) and HER2 antibodies (e.g., trastuzumab)
option C= immunotherapy that targets PD-1, PD-L1 and CTLA-4 enhances immune response against cancer and often used in treatment of malignant melanoma; side effects= autoimmune-related= skin, liver, GI, and endocrine inflammation
option D= vincristine and bortezomib
option E= platinum-based chemotherapy (e.g., cisplatin)
answer: Linking factors IXa and X to create activated X (Xa)
-Hemophilia A (X-linked recessive)= mutations to genes encoding clotting factor VIII
-Factor VIII is part of intrinsic coagulation cascade, it acts as a bridging protein that brings together the catalytic component of factor IXa (the protease) with factor X (the substrate), thereby amplifying formation of factor Xa, which promotes fibrin clots
-Treatment: factor VIII replacement products (e.g., factor VIII concentrate from plasma); long-term efficacy is limited by formation of neutralizing antibodies (factor VIII inhibitors)
-Emicizumab, a bispecific monoclonal antibody, mimics normal physiologic function of factor VIII and can be used to prevent or treat bleeding in patients who have factor VIII inhibitors= this antibody has 2 binding sites= one site to bind factor IXa and the other binds to factor X, which brings them into close proximity and allows factor IXa to cleave factor X into its active form
option A= vWF, large glycoprotein produced by endothelium, aids platelet clot formation by binding platelets to subendothelial collagen at sites of injury; also carrier protein for factor VIII; patients with vWD will have mild deficiencies in factor VIII
option B= extrinsic pathway= tissue trauma= factor VII + tissue factor= factor X activation
option C= vWF multimers are cleaved to smaller subunits by metalloprotease ADAMTS13; loss of ADAMTS13 leads to thrombotic thrombocytopenia purpura
option D= factor XIIIa cross-links loose fibrin molecules into a dense network, thereby forming stable fibrin clots
answer: Abciximab
Patient most likely has Glanzmann thrombasthenia (autosomal recessive)= deficient or defective glycoprotein IIb/IIIa on platelet surfaces= peripheral smear shows no platelet clumping (important clue for diagnosis)
Platelets are responsible for formation of platelet plugs that stop bleeding from injured vessels (primary hemostasis). Vessel wall injuries exposes the subendothelial collagen and matrix. Platelet attachment to exposed collagen is strengthened by GP Ib binding to vWF on vessel wall. The resulting platelet activation leads:
-Release of mediators (e.g., ADP, thromboxane A2) into circulation, which in turn activates other platelets
-Conformational change of GP IIb/IIIa on platelet surfaces; this allows thousands of copies of GP IIb/IIIa to bind fibrinogen, thereby forming a platelet plug
Abciximab, a GP IIb/IIIa inhibitor, inhibits binding of this receptor to fibrinogen. Abciximab and others from this class are useful for treatment of unstable angina and acute coronary syndrome, particularly in patients undergoing PCI
option B= used in heparin induced thrombocytopenia= direct thrombin inhibitor
option C= irreversible COX-1 and 2 inhibitor, inhibits TXA2 via platelet COX acetylation; preventing platelet aggregation
option D= inhibits platelet aggregation by blocking P2Y12 on platelet ADP receptors
option E= used in atrial fibrillation or DVT= direct thrombin inhibitor
option F= potentiates antithrombin III activity, leading to inactivation of thrombin and factor Xa
option G= prevents K-mediated carboxylation of several coagulation factors
answer: medication-induced inhibition of a nucleic acid synthesis enzyme
Patient with sickle cell disease has pancytopenia. Pancytopenia is caused by hematopoietic stem cell dysfunction, bone marrow infiltration, or peripheral destruction of mature blood cells
-Low reticulocyte count: patients with severe anemia usually have increased reticulocytes due to increased bone marrow erythropoiesis. The presence of pancytopenia with an inappropriately low reticulocyte count usually indicates the bone marrow is impaired and is unable to adequately generate new cells despite strong growth signals (e.g., increased EPO)
-Macrocytosis: pancytopenia + macrocytosis= vitamin deficiency (e.g., vitamin B12, folate) or medication (e.g., hydroxyurea) is impairing DNA synthesis in hematopoietic cells
Hydroxyurea inhibits ribonucleoside reductase, an enzyme that generates deoxyribonucleoside triphosphates for DNA synthesis/repair= lack of deoxyribonucleoside triphosphates slow erythrocyte nuclear development= decreased cellular division with overall increase in erythrocyte size= high doses of hydroxyurea also impair nuclear development of precursors of leukocytes and thrombocytes= pancytopenia
Hydroxyurea is the major disease modifying medication in SCD; it reduces production of mutated beta-globulin gene and increases production of fetal hemoglobin gene, which increases HbF (functions normally; RBCs with HbF are less likely to sickle)
option A= autoimmune hemolytic anemia is associated with high reticulocytes due to increased erythropoiesis; reticulocytes have higher MCV than RBCs; but no leukopenia or thrombocytopenia
option B= folate is a methyl group donor for synthesis of purines and pyrimidines; folate deficiency impairs DNA synthesis, can lead to pancytopenia and macrocytosis; but patient is taking folic acid
option C= paroxysmal nocturnal hemoglobinuria is an acquired disorder of hematopoietic progenitor cells marked by lack of complement inhibitors (CD55, and C59) on erythrocyte surface; hemolytic anemia is primary manifestation, reticulocytosis is common, and pancytopenia only rarely occurs
option E= SCD can cause hypersplenism due to splenic congestion with damaged RBCs; can cause pancytopenia, but patients will have splenomegaly and normocytic anemia
answer: Aspirin
-Patients presentation of recent (within 1-3 days) MI, pleuritic chest pain improved by leaning forward, and a friction rub on exam= peri-infarction pericarditis (most improve with supportive measures, those with persistent symptoms are treated with aspirin and colchicine)
-Aspirin (acetylsalicylic acid) is an NSAID that irreversibly inhibits COX-1 and 2 enzymes via acetylation, preventing conversion of arachidonic acid to prostaglandins, prostacyclin and thromboxane
-COX-1 acetylation inhibits generation of TXA2 in platelets (antithrombotic effect). COX-2 acetylation blocks prostaglandin production in inflammatory cells (e.g., activated lymphocytes, neutrophils) resulting in anti-inflammatory, antipyretic and analgesic effect
option A= analgesic and antipyretic, reversibly inhibits COX enzymes, primarily in the CNS, lacks anti-inflammatory properties= weak inhibition of COX in peripheral tissues
option C= glucocorticoid agent with potent anti-inflammatory activity; corticosteroids reduce COX-2 expression and decrease synthesis of arachidonic acid via phospholipase A2 inhibition
option D= selective COX-2 inhibitor, provides anti-inflammatory benefits without interfering with the functions of COX-1; no significant effect on platelet function and are associated with lower incidence of GI bleeding; however, associated with increased risk of thrombosis
option E= exerts anti-inflammatory effects by inhibiting polymerization of beta-tubulin into microtubules, preventing migration and activation of neutrophils
option F, G and H= NSAIDs that reversibly inhibit COX-1 and COX-2
answer: Disruption of intestinal bacterial flora
Warfarin is a vitamin K antagonist= inhibits epoxide reductase in liver, thereby preventing gamma carboxylation of vitamin K-dependent clotting factors (II, VII, IX and X). This creates an anticoagulant state that is reflected on lab assessment as a prolonged INR. Patients are at risk for subtherapeutic or supratherapeutic INR due to:
-Change in dietary vitamin K intake: increased vitamin K intake= more vitamin K in liver= counters inhibitory effect of warfarin on epoxide reductase (eat consistent amount of vitamin K containing foods like leafy greens, brussels sprouts) (Choice E)
-Disruption to intestinal flora: flora produces vitamin K as byproduct; antibiotics that target gram-negative bacteria such as metronidazole, macrolides, fluoroquinolones, can cause supratherapeutic INR due to destruction of vitamin K producing bacteria in gut; administration of antibiotic (e.g., ciprofloxacin) for pyelonephritis likely destroyed bacteria in gut= reducing vitamin K production
-Alteration to cytochrome P450 2C9 activity (P450 2C9 degrades warfarin); 1) phenytoin, carbamazepine and rifampin increase P450 2C9 activity= subtherapeutic INR (choice D) 2) metronidazole, fluconazole, and amiodarone inhibit P450 2C9 activity= supratherapeutic INR
option A= aspirin; interferes with platelet aggregation= prolongs bleeding time, not INR
option C= can occur due to recent pregnancy, malignancy, or rheumatologic disease; most cases involve inhibition of factor VIII, which leads to bleeding diathesis and prolonged aPTT (not INR, which reflects PT)
answer: Xanthine oxidase
-6-MP can be administered directly or in its prodrug form (i.e., azathioprine). Following ingestion, 6-MP is converted by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanine (6-TG) active metabolites (choice C)
-The 6-TG metabolites are purine analogues that act as false nucleotides to disrupt DNA and RNA synthesis and inhibit proliferation of hematopoietic cells, a useful effect in treatment of autoimmune diseases, organ transplant rejection, and some types of cancer (e.g., leukemia)
-6-MP is metabolized into inactive metabolites by 2 different enzymes, xanthine oxidase and thiopurine methyltransferase (TMPT), both of which are clinically important
-Coadministration of 6-MP with a xanthine oxidase inhibitor (e.g., allopurinol, febuxostat) slows inactivation of 6-MP and shunts metabolism toward the production of 6-TG active metabolites, therefore, the dose of 6-MP should be reduced
-In addition, roughly 12% of population has a genetic mutation resulting in low or absent activity of TMPT, creating a high risk of toxicity with administration of 6-MP; therefore, some clinicians recommend that patients undergo genetic testing for TMPT activity prior to initiating 6-MP or azathioprine therapy
option A= converts adenosine to inosine as part of purine metabolism; this enzyme is deficient in severe combined immunodeficiency but may be overexpressed in some malignancies; Cladribine, which is used in treatment of hairy cell leukemia, is a cytotoxic purine analogue resistant to degradation by ADA
option B= methotrexate is used in treatment of cancer and rheumatologic disease; inhibits dihydrofolate reductase= blocking conversion of dihydrofolate to tetrahydrofolate and disrupting synthesis of thymidine and, to lesser extent purine
option D= MOA inhibitors are used in treatment of atypical depression; these agents inhibit degradation of norepinephrine, dopamine and serotonin
option E= Cyclophosphamide, used to treat many types of cancer, requires bioactivation by cytochrome P450 mixed function oxidase system
option F= inhibited by chemotherapeutic agents etoposide and teniposide
answer: Clotting factors generated before warfarin initiation
-Warfarin is a vitamin K antagonist that blocks epoxide reductase in the liver, leading to impaired vitamin K recycling= depletes reduced form of vitamin K, which is required for gamma carboxylation of vitamin K dependent clotting factors (II, VII, IX, and X)
-In absence of gamma carboxylation, vitamin K dependent clotting factors cannot bind calcium or phospholipid membranes to induce coagulation
-Because warfarin inhibits gamma carboxylation of new vitamin K-dependent clotting factors, therapeutic efficacy is delayed until preexisting clotting factors in the plasma are consumed. Although INR tends to slowly increase in the first few days of administration due to short half-life of factor VII (4-6 hours), full therapeutic effect does not typically occur for 3 days due to long half-life of factor II
-Warfarin also inhibits gamma carboxylation of proteins C and S (short half-life). Because these proteins exert an anticoagulant effect, initiation of warfarin can be associated with initial procoagulant state
option B= cause heparin induced thrombocytopenia, which typically arise 5-10 days after heparin initiation; condition marked by thrombocytopenia and high risk of arterial and venous thrombosis, but would not result in a delay in therapeutic INR following warfarin administration
option C= doesn't contribute to warfarin efficacy; increased intake of vitamin K rich food can lead to subtherapeutic INR due to increased vitamin K availability in the liver
option D= warfarin is metabolized by P450 2C9; can cause drug interactions
option E= warfarin reaches maximal plasma concentration approximately 90 mins after administration
answer: Depletion of endothelial growth factors for angiogenesis
-Wound dehiscence is partial or complete separation of previously approximated wound edges. It occurs due to disruption of the wound-healing process and may be a complication of medications such as bevacizumab
-Bevacizumab is a monoclonal antibody that binds vascular endothelial growth factor (VEGF), preventing it from binding to its cell surface receptor. This inhibits angiogenesis- the process by which new blood vessels sprout from surrounding, uninjured vessels and grow into the wound- because angiogenesis is largely stimulated by VEGF
-Because bevacizumab suppresses growth of new blood vessels, it limits blood supply to tumor and is often referred to as cancer-starving therapy. However, because it also suppresses angiogenesis in healing wounds, it can cause wound dehiscence
-The lack of angiogenesis leads to inadequate blood supply to support collagen production during the proliferation phase (3 days to 5 weeks) and collagen remodeling and cross-linking during the maturation phase (3 weeks to 2 years)= when these are inhibited, the tensile strength of the wound remains low and dehiscence can occur even weeks to months after initial wound closure
option B= radiation therapy, commonly used in cancer treatment, causes DNA damage, resulting in apoptosis of susceptible (e.g., highly proliferative) cells; however, it damages surrounding noncancerous tissues, including local blood vessels, which can subsequently develop progressive eccentric myointimal proliferation and luminal obstruction
option C= Vinca alkaloids such as vincristine and vinblastine inhibit cytoskeleton microtubule development; results in arrest of cell division and replication at the metaphase stage, leading to apoptosis
option D= anti-inflammatory agents like glucocorticoids and thus, delay wound healing
option E= vitamin C deficiency can result in inadequate hydroxylation of proline and lysine residues during collagen synthesis; hydroxyproline and hydroxylysine are essential for collagen cross-linking= vitamin C deficiency reduces maximal tensile strength of wound
answer: Higher number of cancer neoantigens
The genetic mutations that drive oncogenesis also create unique proteins not found in healthy cells. Antigens from these proteins (neoantigens) are displayed on the surface of tumor cells and may be subsequently recognized by patrolling cytotoxic T cells as "not self" and destroyed
Cancers with defects in mismatch repair proteins and high microsatellite instability (reflecting DNA polymerase errors during replication) are particularly susceptible to immune recognition because they rapidly accumulate mutations and generate 20-fold more neoantigens than tumor cells that have normal mismatch repair. Cancer cells use a wide range of mechanisms to thwart cytotoxic T cell detection, including:
-Downregulating cell surface receptors involved in immune recognition; for instance, decreased expression of MHC leads to decreased neoantigen presentation on surface of cells
-Overexpressing cell surface proteins that inhibit the immune response; For instance, cancer cells can overexpress programmed death-ligand 1 (PD-L1), which binds to programmed cell death-1 (PD-1) receptor on the T-cell surface and inhibits the cytotoxic T cell response (T-cell exhaustion)
Cancer cells that overexpress PD-L1 are less susceptible to cytotoxic T cell-mediated destruction (enhanced T-cell exhaustion). These tumors can be treated with monoclonal antibodies that block PD-1 receptor on T cells (e.g., pembrolizumab, nivolumab) or the PD-1 ligand on cancer ells (e.g., atezolizumab). Treatment stimulates cytotoxic T cell response, it is particularly effective against tumors with large quantities of neoantigens (e.g., those with deficits in mismatch repair) because these tumors are particularly susceptible to recognition as "not self"
option A= multidrug transport that can be used by cancer cells to pump cytotoxic chemotherapy out of the cell
option C= proto-oncogene that is part of the signaling pathway for the epidermal growth factor receptor. Tumors with activating KRAS mutations are resistant to monoclonal antibodies against epidermal growth factor receptor because they have an activating mutation in a downstream signal
option D= tumor suppression protein that inhibits cellular replication when DNA is damaged and induces apoptosis; mutations to p53 can lead to unregulated cellular growth and may inhibit cytotoxic chemotherapy-mediated cancer cell apoptosis
option E= desmoplasia (dense fibrosis) around a tumor can reduce the ability of cytotoxic chemotherapy to enter cancer cells
answer: Increased fetal hemoglobin synthesis
-Patients with sickle cell disease have a missense mutation in the beta globin gene that leads to substitution of valine for glutamic acid in the 6th position of the beta globin chain= altered form is called hemoglobin S; unlike normal adult hemoglobin (HbA), HbS polymerizes when deoxygenated or dehydrated, leading to erythrocyte membrane damage (i.e., intravascular hemolysis) and clogging of small vessels (e.g., painful vasoocclusive crises, ischemia)
-Heterozygotes for Hb S are usually asymptomatic because there is enough HbA to prevent extensive polymerization of Hb S, but homozygotes typically have severe disease. These individuals often require repeated blood transfusions for symptomatic anemia and treatment with hydroxyurea, an antimetabolite that inhibits the ribonucleotide reductase enzyme
-Although inhibition of ribonucleotide reductase leads to the myelosuppressive effects of hydroxyurea (it causes cell cycle arrest in rapidly dividing hematopoietic cells), hydroxyurea also shifts globin gene transcription from beta globin locus to the gamma globin locus (via unclear mechanisms), thereby increasing circulating levels of fetal hemoglobin (HbF)
-HbF is unaffected by sickle cell mutation (not composed of beta chains) and has physiologic properties similar to HbA2, therefore, hydroxyurea is often used in treatment of SCD to improve oxygen delivery, reduce vasoocclusive crises, and lessen need for transfusions
option A= the calcium-dependent (Gardos) potassium channel regulates the transport of potassium and water through the erythrocyte membrane, blocking this channel could help prevent erythrocyte dehydration, doesn't improve symptoms though
option B= Voxelotor directly inhibits polymerization of HbS by binding to the alpha chain of the molecule and causing an allosteric change that results in increased oxygen binding
option C= can help with disease; but not hydroxyurea mechanism
option E= L-glutamine, a precursor to antioxidant glutathione, reduces oxidative stress in erythrocytes with Hb S; used in patients with SCD who have persistent vasoocclusive pain or those who can't tolerate hydroxyurea
option F= via erythropoietin would likely worsen vasoocclusive crises by increasing circulating levels of HbS; hydroxyurea inhibits synthesis of RBCs, WBCs and platelets by blocking ribonucleoside reductase, but patients still benefit from administration due to stimulated HbF production
answer: Neurokinin-1
-Vomiting is a reflex that can be activated by either humoral or neuronal stimuli
-Area postrema in the 4th ventricle has a chemoreceptor trigger zone that can respond to many neurotransmitters, drugs or toxins
-The nucleus tractus solitarius (NTS) in the medulla receives information from the area postrema, GI tract via vagus nerve, vestibular system and CNS (e.g., meninges, hypothalamus). Neurons from NTS project to other medullary nuclei and coordinate the vomiting process
-The 5 major receptors involved in stimulating the vomiting reflex in the area postrema and adjacent vomiting center nuclei are M1 muscarinic, D2 dopaminergic, H1 histaminic, 5-HT3 serotonergic, and neurokinin 1 receptors
-5-HT3 receptor antagonists (e.g., ondansetron) and dopamine receptor antagonists (e.g., metoclopramide) are particularly helpful for chemotherapy-induced vomiting. When these do not control symptoms, NK1 receptor antagonists (prevent substance P releases) can be considered, they prevent both acute vomiting and delayed emesis associated with chemotherapy
option A= opioid receptor antagonists (e.g., naltrexone) competitively bind opioid receptors to prevent action of endogenous or exogenous opioids. They are used mainly for opioid dependence
option B= regulates interdigestive migrating contractions. Erythromycin is a motilin receptor agonist used for gastroparesis
option D= is a polypeptide neurotransmitter found in the CNS and ANS. It is thought to play a role in appetite and pain perception. NPY antagonists have been investigated as potential antiobesity drugs
option E= nicotinic antagonists are primarily used for muscle paralysis during surgery. Some antihistamines (e.g., promethazine, meclizine) and antimuscarinics (e.g., scopolamine) have anticholinergic activity and inhibitory effects on both the vomiting center and vestibular apparatus= useful for motion sickness
answer: option D (Drug X: methotrexate; Drug Y: fluorouracil)
-Methotrexate is a folic acid analog that functions by binding and inactivating dihydrofolate reductase, an enzyme responsible for reducing folic acid to tetrahydrofolate
-Tetrahydrofolate participates in the transfer of carbon groups in certain intracellular reactions including purine and thymidine synthesis
-5-fluorouracil is a pyrimidine analog that primarily functions to inhibit DNA synthesis by inhibition of thymidylate synthetase after enzymatic conversion to its nucleotide floxuridine monophosphate
-Methotrexate prevents reduction of folic acid to tetrahydrofolate, while 5-FU binds THF and thymidylate synthetase in a stable-reaction intermediate form, thereby effectively decreasing the amount of thymidylate synthetase available for thymidine synthesis
-Leucovorin (N5-formyl-tetrahydrofolate) is a tetrahydrofolate derivative that does not require reduction by dihydrofolate reductase before it can function as a cofactor for thymidylate synthase and other enzymes involved with purine and amino acid synthesis (it bypasses dihydrofolate reductase; thus, can be used for methotrexate toxicity)
-5-FU requires presence of THF in order to form complexes with thymidylate synthetase (5-FU= reduced cytotoxicity in cells that are deficient in THF); leucovorin can be used to potentiate toxicity of 5-FU by helping bind thymidylate synthetase
option A= cytarabine like 5-FU is a pyrimidine analog antimetabolite that is incorporated into DNA leading to strand termination= doesn't affect folate metabolism; Gemcitabine is another pyrimidine analog that functions like cytarabine, but it is not S-phase specific due to inhibition of ribonucleotide reductase
option C= Fludarabine is a deamination-resistant purine analog, inhibits DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase; used to treat CLL
answer: Enoxaparin
Pregnancy increases risk of venous thromboembolism due to anatomic changes (e.g., uterine compression of IVC and iliac veins) and physiologic hypercoagulability (e.g., increased production of clotting factors, decreased protein S levels, protein C resistance)
Heparins are ideal anticoagulants for most pregnant women as they do not cross placenta and the risk of fetal bleeding and teratogenicity is low
-Low molecular weight heparin (e.g., enoxaparin, dalteparin) is preferred as it has a relatively long half-life (4.5 hours) and does not require routine lab monitoring. However, it is renally cleared and can't be used in patients with severe renal insufficiency (creatinine clearance <30ml/min)
-Unfractioned heparin (short half-life: 1-2 hours) and requires frequent lab draws (i.e., PTT) due to its more varied anticoagulant effect. However, it may be used in patients with renal insufficiency; also used in place of LMWH at term (37 weeks gestation) as it can be discontinued at onset of labor to minimize hemorrhagic risk
option A and C= direct thrombin inhibitors are not recommended in pregnancy; fetal toxicity
option B= no role in VTE treatment; blocks ADP receptor; used in coronary artery disease, acute coronary syndrome, and prevention of recurrent ischemic stroke
option E= prescribed to certain pregnant patients at risk of preeclampsia
option F= used in clot lysis; high risk of major bleeding and is reserved for those with massive deep vein thrombosis at risk of limb ischemia or life-threatening pulmonary embolism with hypotension
option G= crosses placenta, increasing risks of teratogenicity and fetal hemorrhage, avoided in pregnancy
answer: Chemotherapy-induced nausea
Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer treatment. It is caused by both peripheral and central mechanisms, as follows:
-acute-phase CINV (<24 hours after chemotherapy) is mediated primarily by the release of serotonin from intestinal enterochromaffin cells that have been damaged by chemotherapy. Serotonin stimulates vagal afferent fibers (5-HT3) in the bowel wall, which project to the brainstem and stimulate the vomiting reflex. Therefore, serotonin receptor antagonists (e.g., ondansetron) can be used for treatment
-Delayed-phase CINV (1-5 days after chemotherapy) is mediated primarily by increased levels of substance P in the brainstem due to chemotherapy-associated emetic stimuli in the CSF and bloodstream. Substance P binds to and activates the NK-1 receptor in CTZ, area postrema, nucleus tractus solitarius. Therefore, NK-1 antagonists (e.g., aprepitant, fosaprepitant) are often used
Usually both combined to inhibit both types of CINV
option B= is loss of muscle and fat caused by elevated levels of circulating inflammatory cytokines. Progesterone analogs (e.g., megestrol acetate) are first-line treatment, corticosteroids and cannabinoids are also used
option C= treated with bisphosphonates (e.g., zoledronic acid), which reduce osteoclast-mediated bone resorption
option D= occurs due to opioid-mediated effects on the bowel wall, which reduce peristalsis; methylnaltrexone, an opioid antagonist that has limited ability to cross the BBB (doesn't trigger withdrawal), can be used as treatment
option E= patients who have highly aggressive lymphomas and leukemias are at risk of tumor lysis syndrome with chemotherapy. Its primary manifestation is renal damage from elevated uric acid levels (catabolism of nucleic acids released from tumor cells increases uric acid). Rasburicase, a drug that breaks down uric acid, is used to prevent TLS in high-risk patients
answer: Induces free radical formation and DNA strand breaks
-Bleomycin is commonly used in treatment of Hodgkin lymphoma and germ cell tumors; exerts antineoplastic effect by binding iron and oxygen molecules to create free radicals that cause DNA strand breaks; lung toxicity, usually in form of pulmonary fibrosis, is the most clinically important adverse effect of drug
-Mechanism: oxidative free-radical damage to healthy tissue, leading to a cycle of tissue damage and repair; lungs are susceptible because they lack bleomycin hydrolase (inactivates it)
-Symptoms: dyspnea, nonproductive cough, and crackles on lung auscultation (within 6 months of therapy); bibasilar interstitial opacities are typically seen on chest x-ray and spirometry shows reduced FVC with preserved FEV1, consistent with a restrictive pattern (in addition there is reduced diffusion capacity for carbon monoxide due to impaired gas exchange across fibrosed interstitium
option A= Vinca alkaloids (e.g., vincristine, vinblastine) bind to beta-tubulin to disrupt microtubule polymerization and prevent mitotic cell division; peripheral neuropathy is most common side effect
option B= 5-FU inhibits thymidylate synthase to impair DNA synthesis; bone marrow suppression can occur
option D= Etoposide inhibits topoisomerase II to cause DNA strand breaks, and is commonly associated with bone marrow suppression; anthracyclines (e.g., doxorubicin) also exert at least part of their antineoplastic effect by binding to topoisomerase II and cause cardiotoxicity= dilated cardiomyopathy
option E= imatinib and erlotinib are used to treat CML and lung cancer respectively; disrupt cellular replication and commonly cause diarrhea and skin rash
option F= e.g., Bortezomib is used in treatment of multiple myeloma; these drugs can cause bone marrow suppression and sometimes peripheral neuropathy
answer: ATP-dependent transporter
-Human tumor cells have developed ability to resist chemotherapy in much the same way that many bacteria have developed resistance to antibiotics
-Mechanism of human tumor cell resistance: via human multidrug resistance (MDR1) gene
-The prototype product of this gene= P-glycoprotein, a transmembrane protein that functions as an ATP-dependent efflux pump
-P-glycoprotein is normally expressed in intestinal and renal tubular epithelial cells and functions to eliminate foreign compounds from the body
-Also present in capillary endothelium of vessels= forms BBB= prevents penetration of foreign compounds into CNS
-In tumor cells, this ATP-powered transmembrane pump protein actively removes chemotherapeutic agents, particularly hydrophobic agents like the anthracyclines
-Drugs such as verapamil, diltiazem, and ketoconazole, among others, have been shown to reduce the action of the MDR1 protein
option A= mediate effects of hormones that promote anabolism and cell growth such as insulin, IGF-1, EGF, PDGF, and others
option B= utilized by beta-adrenergic receptors, V2 ADH receptors, calcitonin, glucagon, TSH, ACTH, and HCG receptors, and others
option C= CAMs are proteins located on cell surface that mediate binding with other cells or with the ECM; e.g., selectins, integrins, and cadherins; cell adhesion molecules are generally downregulated in malignant tumors, which allows these cells to spread from their site of origin
option D= selectively allow certain ions to pass into or out of cell
answer: Dihydrofolate polyglutamate
-Methotrexate, a folate antagonist, is the drug of choice for non-surgical treatment of an early, unruptured ectopic pregnancy
-Folic acid is a required precursor to nucleic acid synthesis; barriers to its metabolism are especially effective in hindering the growth of rapidly proliferating cells such as in a developing embryo or certain types of cancer
-Normally, folic acid is reduced to dihydrofolate (DHF) by dihydrofolate reductases and then reduced further to tetrahydrofolate (THF), an integral precursor of DNA synthesis
-MTX is structurally similar to folic acid and competitively and irreversibly inhibits DHF reductase (prevents formation of THF; option D)
-After entering target cells, MTX undergoes polyglutamation, which prevents movement of MTX out of cell, resulting in intracellular accumulation of MTX for later use; similarly, folate and recycled DHF are stored within the cell via polyglutamation; because MTX inhibits DHF reductase, folic acid and DHF polyglutamate will accumulate in cells
option B= leucovorin is a reduced form of folic acid that can be used to counter toxic effects of MTX chemotherapy; Folinic acid selectively rescues normal cells by competing with MTX for DHF reductases binding sites; it can reactivate DHF reductase
option C= PABA is a folic acid precursor for prokaryotes; sulfonamide antibiotics are chemical analogs of PABA that inhibit the enzyme dihydropteroate synthetase, preventing bacterial conversion of PABA to folic acid; humans lack ability to convert PABA to folic acid and require dietary folate
option E= is a nucleotide that contributes to pyrimidine formation; its synthesis is inhibited by MTX
answer: M
-Diffuse large B cell lymphoma (most common type of non-Hodgkin lymphoma) has peripheral neuropathy likely due to vincristine
-The vinca alkaloids (e.g., vincristine, vinblastine)= inhibit microtubule formation (they bind beta-tubulin, preventing polymerization of microtubule proteins)= cell-cycle specific cytotoxicity (during the M phase) as the replicated chromosomes are unable to align and subsequently unable to segregate into daughter cells
-Vincristine is most classically associated with neurotoxicity, which is often dose-related and most commonly present as peripheral neuropathy
-Neurotoxicity likely results from disruption of neuronal microtubules, which are responsible for transporting organelles and other cellular products between the neuronal cell body and axon terminals
-Taxanes also inhibit M phase
-Some agents are cell-cycle nonspecific; cyclophosphamide (alkylating agent that causes bone marrow suppression, alopecia, and hemorrhagic cystitis)
option A= resting stage
option C= cells in this phase prepare the building blocks for DNA synthesis
option D= DNA replication during this phase; topoisomerase I and II inhibitors (e.g., etoposide, irinotecan) as well as antimetabolites (e.g., methotrexate, 5-fluorouracil) function during this phase
option E= DNA is checked for errors and corrections are made if possible; If corrections can't be made then apoptosis will result unless loss-of-function mutations to the genes controlling this process are present, a condition frequently encountered in tumor cells; drugs that intercalate DNA and induce free radical formation function here (bleomycin= causes pulmonary fibrosis; doxorubicin= cardiomyopathy
answer: Prothrombin time
-ECG= suggests atrial fibrillation, which alters cardiac flow dynamics, making thrombus formation more common
-If thrombus detaches from atrial wall= risk of stroke
-Oral anticoagulant warfarin (coumadin) reduces thrombus formation risk by inhibiting activation of vitamin K dependent clotting factors II, VII, IX, X (vitamin K antagonist)= decreased levels of these factors, particularly factor VII, and therefore prolongs prothrombin time
-Another useful lab value is the INR, a ratio of the patient's PT to a control (usual INR target for AF: 2.0-3.0)
-Examples of indications include AF, DVT, and PE; outpatients who take warfarin typically have their INR checked every few weeks (more frequently initially)
-Most common side effect= excessive anticoagulation leading to bleeding (which can require vitamin K and fresh frozen plasma if rapid reversal is needed);
-skin necrosis can occur during the first few days of treatment due to transient hypercoagulable state (reduction in protein C anticoagulant activity before affecting other coagulating factors)= for this reason, heparin is typically administered temporarily at the start of warfarin therapy ("heparin bridge").
-Warfarin should not be used during pregnancy because it is teratogenic and can cause fetal bleeding
option A= used to monitor unfractioned heparin which primarily affects intrinsic coagulation pathway
option B= used for assessment of platelet function; increased bleeding time can be seen with thrombocytopenia, vWD, defects of platelet aggregation, DIC and aspirin therapy
option C and D= decreased in DIC
answer: Increased activation of caspases
-lymphadenopathy, splenomegaly, and increased number of mature lymphocytes in blood that express B-cell marker (CD20+, kappa light chains) indicate chronic lymphocytic leukemia (CLL)
-Disease is characterized by progressive accumulation of mature B cells in hematopoietic tissues (leading to anemia, thrombocytopenia, lymphadenopathy, and splenomegaly) and peripheral blood (leading to leukocytosis) due to genetic mutations that lengthen B-cell survival
-In most cases of CLL, B-cell survival is promoted by the overexpression of BCL-2 on the mitochondrial membrane; BCL-2 is an antiapoptotic protein that prevents stress signals from triggering the intrinsic apoptotic cascade, which is mediated by release of cytochrome C from the mitochondria and subsequent activation of caspases
-Treatment of CLL with BCL-2 inhibitors (e.g., venetoclax) makes tumor cells more sensitive to stress signals (e.g., chemotherapy) by increasing activation of caspases, which leads to cell death
option A= Bortezomib, proteasome inhibitor that prevents destruction of ubiquinated intracellular proteins, can be used against neoplasms that generate excessive amounts of proteins; e.g., multiple myeloma
option B= tumor cells produce neoantigens not seen in normal cells, they generally have mutations that allow them to evade cytotoxic T cell detection; immune checkpoint inhibitors, such as antibodies against PD-1 (pembrolizumab) or CTLA-4, prevent cancer cells from evading cytotoxic T cell detection
option D= Olaparib inhibits poly-ADP ribose polymerase, the enzyme that mediates the repair of single-stranded DNA breaks; often used to treat breast, ovarian, or prostate cancer in individuals with BRCA mutations
option E= many drugs target this, antimetabolites (e.g., purine analogs)
option F= Rituximab is a monoclonal antibody against B cell surface marker CD20; often used for CLL, it mediates cell death by binding to the B-cell surface= antibody-mediated cytotoxicity
answer: Medication-associated adverse effect
Takes carbamazepine, developed pancytopenia with normal morphology= drug-induced aplastic anemia; aplastic anemia (form of bone marrow failure caused by damage to multipotent hematopoietic stem cells); most are due to direct toxicity to hematopoietic stem cells or alteration of stem cell surface antigens (leads to destruction by cytotoxic lymphocytes)
Aplastic anemia can be idiopathic; often triggered by ionizing radiation, toxic chemicals, viral infections, or medications; drug-induced AA is categorized as follows:
-dose-dependent reactions are caused by medications (e.g., chemotherapy, immunosuppressives) that are toxic to bone marrow when drug levels exceed certain concentration of a certain period (predictable in onset)
-Idiosyncratic reactions are often caused by antiseizure medications (e.g., carbamazepine, valproic acid), sulfonamides, or nifedipine; they are unpredictable, unrelated to dose of drug, and may occur at any point of therapy (mechanism is unclear, likely genetic mutations in metabolizing enzymes or efflux pumps)
Because multipotent hematopoietic cells generate all mature blood cells, patients with AA usually have signs of pancytopenia (petechiae, bleeding; pale mucous membranes; infections); biopsy= hypocellular marrow with lipidoses
option A= autoantibodies not part of aplastic anemia mechanism
option B= leads to hypersegmented neutrophils, macrocytic RBCs on peripheral smear because of delayed nuclear maturation
option D= hypersplenism can cause sequestration with increased destruction of blood cells in splenic sinusoids; most cases arise in those with portal hypertension, which leads to increase in splenic volume and activity; cytopenia can occur, but usually mild and doesn't cause symptoms
option E= associated with clot formation in microvasculature and shearing of red blood cells, leading to thrombocytopenia (e.g., petechiae) and anemia; peripheral blood smear would reveal schistocytes
answer: Converting uric acid into more soluble metabolites
Tumor lysis syndrome (TLS) is an oncologic emergency that primarily develops during initial chemotherapy for high-grade lymphomas, leukemias, and other cancers with rapid cell turnover, substantial tumor burden, or high sensitivity to chemotherapy. When large numbers of tumor cells are destroyed in a short period, massive quantities of intracellular tumor products are released into circulation, which frequently result in:
-hyperkalemia= arrhythmias
-Hyperphosphatemia= precipitates calcium in renal tubules and collecting system= systemic hypocalcemia and acute renal injury from calcium-phosphate stones
-Hyperuricemia= precipitates urate crystals in renal tubules= acute renal injury
Aggressive IV fluids during and after chemotherapy can help prevent kidney injury by flushing metabolites out of kidneys. Treatment with agent that reduces formation of uric acid also used to limit formation of uric acid stones; including one of the following:
-Rasburicase (recombinant version of urate oxidase; an enzyme present in mammals, but not humans)= urate oxidase converts uric acid into allantoin, a purine metabolite that is 5-10 times more soluble than uric acid and therefore less likely to precipitate in kidneys
-Allopurinol is a purine decoy=competitively inhibits xanthine oxidase= reduces conversion of purine metabolites to uric acid (choice C); febuxostat is non-purine selective inhibitor of xanthine oxidase
option B= phosphate binders; e.g., sevelamer; are used to manage hypophosphatemia in patients with chronic kidney disease
option D= mesna can prevent hemorrhagic cystitis in patients receiving cyclophosphamide or ifosfamide, it supplies a thiol group that inactivates the toxic metabolite (acrolein) of these chemotherapeutics
option E= Folinic acid (leucovorin) provides a reduced form of folic acid to counter the methotrexate-induced block in folic acid metabolism; it rescues GI mucosa and bone marrow cells from effects of MTX