Heme/Onc Part 2 Flashcards
Role of ADP, TxA2, PGI
TxA2 and ADP activate platelets by binding to P2Y1 and P2Y12 which inhibit adenylyl cyclase which decreases cAMP which decreases PKA activity which increases platelet activities
-PGI has the opposite effects
White (arterial) thrombus vs Red (Venous) thrombus
- Arterial thrombus can be prevented by anti platelet drugs
- Venous thrombus can be prevented by anticoagulants and existing thrombosis can be treated with thrombolytics
Antiplatelet drugs
Inhibit aggregation of platelets thus reducing risk of thrombus in arterial circulation.
COX-1 inhibitors
Inhibit COX-1 which leads to decreased TxA2 levels
Phosphodiesterase inhibitors
- dipyridamole
- PDE inhibits cAMP degradation which leads to increase PKA activation and causes decreased aggregation
- Combined with fixed dose of aspirin to reduce risk of stroke
Clopidogrel
- ADP receptor antagonist
- prodrug (CYP2C19)
- Binds irreversibly to P2Y12 ADP receptor subtype and prevents activation of GPIIB/IIIA
- Effects last 7 days (time to synthesize new platelets
- PK: orally effective with anti platelet action beginning in 2 days and reach max at 8-11 days (loading dose to reach maximum effect in 2 hours)
- USES: reduces rate of CVA, MI, and death in atherosclerotic patients -or- in combo w/ aspirin to prevent coronary stent thrombosis
- Failure in patients w/ loss of CYP2C19
- TTP rare but life threatening
- Avoid in patients with bleeding disorders
Abciximab
- GPIIB/IIIA Antagonists
- Fab fragment of a monoclonal antibody blocks fibrinogen binding
- IV 48hr half life due to irreversible binding of antagonist
- Most effective drug but it’s expensive
- Used short-term in combo w/ heparin to prevent ischemic events in ACS or PCI
- AE: GI and cerebral bleeds, reversed by infusion of donor platelets -or- anaphylaxis and thrombocytopenia due to antibodies against chimeric protein (risk increases with subsequent doses within short time frame)
Anticoagulant drugs
- Inhibit one or more of various steps in coagulation cascade to suppress formation of fibrin clots and reduce risk of venous thrombosis
- Decrease risk of DVT/PE, MI, and ischemic stroke
Heparin (unfractionated)
- Unfractionated
- Heterogenous mix of sulfated mucoploysaccharides that is highly (-) charged and extracted from porcine intestinal mucosa
Enoxaparin
- LMWH
- Prepared from heparin by gel filtration chromatography
Fondaparinux
-Synthetic pentasaccharide that contains the minimum # of heparin SO4 groups to bind antithrombin
Heparins (ALL OF THEM) MOA and PK
-MOA: Accelerate normal rate of inactivation by antithrombin by serving as a catalytic surface for antithrombin and proteases that make antithrombin more active
-Inhibits only circulating clotting factors and onset is rapid
-Heaprin (IIa and Xa equally) LMWH (Xa) Fonadparinux (Xa w/o effects on IIa)
PK: IV infusion and cleared by reticuloendothelial system
-Binds plasma proteins, mononuclear, and endothelial so drug levels = inconsistent and activity must be monitored (PTT)
-LMWH Fondaparinux given SC and cleared by kidneys NO MONITORING
Heparins (AE and USES)
USES: Initial treatment of DVT/PE
-During PCI, open heart surgery, renal hemodialysis to prevent thrombi
-Used in Combo with anti platelet agents for acute coronary syndromes
-LMWH and Fondaparinux have replaced heparin and are used in outpatient
-CAN BE USED DURING PREGNANCY
AE: Bleeding can be combated with protamine sulfate that binds to anionic heparin to form an inactive complex (inactive against fondaparinux)
-Heparin induced thrombocytopenia in first 5-14 days when IgG antibodies bind to heparin platelet factor 4 complex (IgG tail binds IIa receptors on platelets causing aggregation) this risk in higher in fondaparinux and LMWH
-Alternative anticoagulant is needed while heparin is withdrawn (fondaparinux and bivalirudin but not warfarin )
Warfarin
- Vitamin K antagonist that inhibit VKORC 1 (which turns epoxide back to reduced form)
- II VII IX X all depend on vitamin K for carboxylation
- W/O carboxylation these factors have decreased activity
- C and S also depend on vit K so this may create a hyper coagulable state b/c C has the shortest half life of all factors
Warfarin: PK USEs and Pharmacogenetics
PK: 99% bound to albumin and metabolized by 2C9
-Target INR 2-3
USES: Long term prophylaxis of venous thrombosis
-Prevent progression or recurrence of DVT/PE following an initial course of heparin
-Prevent thromboembolism in pts with prosthetic heart valves, a fib, or post MI
-NOT FOR EMERGENCIES
Pharmacogenetics:
-2C9 *2 and *3 = reduced warfarin clearance
-VKORC1 haplotype A = reduced enzyme activity and achieve target INR more rapidly (substantial dose reduction)
Warfarin: Adverse effects and Drug interactions
Adverse Effects:
-Bleeding if INR is too high (intracranial)
-Vitamin K (phytonadione) restores hepatic synthesis of clotting factors when INR > 10 and reduces INR within 24-48 hrs
-With life threatening hemorrhage infusion of 4-factor prothrombin complex concentrate or fresh frozen plasma
-Teratogen,
-Skin necrosis especially in protein C or S deficiency
-Purple toe (cholesterol emboli
-anaphylaxis/hypersensitivity
Drug Interactions:
–Drugs that inhibit 2C9, displace from albumin, broad spectrum antibiotics (less vitamin K), and anything that promotes bleeding –> bleeding
-Inducers of CYP and excessive intake of vitamin K reduce warfarin efficacy and lead to thrombosis (low INR)
Bivalirudin
- Direct inhibitor of Thrombin (IIa) and Factor (Xa)
- recombinant peptide of leech saliva
- Binds reversibly to catalytic and substrate recognition sites of thrombin to prevent it from activating fibrinogen
- IV and monitor by aPTT
- Inactivated by proteases and excreted by kidneys
- Used during PCI with anti platelet drugs and HITT
Dabigatran Etexilate
Oral thrombin inhibitor
- prodrug that is metabolized to competitive inhibitor of thrombin (binds only active site)
- Onset 2-3 hrs excreted renally, shorter t1/2 makes missing a dose a big deal
- Taken 2x/day w/o INR
- Approved for prevention of Stroke in Pts with non-valvular atrial fib (NOT PROSTHETIC HEART VALVES)
- Predictable response
- Bleeding side effect which is less severe than warfarin but no specific antidote
Thrombolytic Agents
- Used to lyse pre-exisiting clots and restore vessel patency in MI, pulm embolism, and stroke
- MUST BE GIVEN WITHIN first 3-6 hrs after event
- Administered via arterial catheter directly to the site of occlusion to lyse large venous thrombus
t-PA (alteplase)
- Thrombolytic
- Recomb. human serine protease
- inactive plasminogen –> plasmin that digests fibrin confines fibrinolysis to clots
- IV w/ T1/2 5 min
- AE produce systemic lytic state that can result in hemorrhage and can also dissolve necessary clots
Ferrous Sulfate
-IRON DEFICIENT ANEMIA
-Oral preparation but all formulas vary in amount of elemental iron
-150-200 mg/day spaced between 3X to avoid GI effects
-Therapy is for 3-6 months after the anemia is corrected or prophylaxis during pregnancy
AE:
-GI disturbances: Naseau, heartburn, constipation, and diarrhea (fade with time)
-Iron toxicity: Hepatic failure, and pulmonary edema, usually in kids, Treat with deferoxamine
-Interactions: antacids reduce absorption and decreases absorption of tetracycline
Iron Dextran
- Iron Deficient Anemia
- Rate of response = ferrous sulfate
- Given when oral iron is intolerable or can’t replenish iron supply fast enough
- W/ Chronic use it’s important to monitor ferritin levels to prevent Iron overload
- Anaphylaxis fro dextran may occur (rare)
B12 deficiency anemia
- Megaloblastic anemia due to impaired DNA synthesis
- Nerve demyelination (can’t be reversed with Folic acid) recovery is slow
Cyanocobalamin
- Treatment for B12 deficiency
- Parenterally, orally, or intranasally
- Oral route is preferred but requires adequate amounts of intrinsic factor
- Severe deficiency requires parenteral admin with Folic acid and RBC/platelet transfusion
- Hypokalemia from excessive utilization in hematopoiesis
Folic acid deficiency
- Identical to B12 deficiency but it doesn’t affect the nervous system
- Usually due to a poor diet or alcoholism
Folic Acid
- You know what it is for
- Folic acid is converted to active form rapidly after administration but it is a vit b12 process
Epoetin alfa
- Erythropoietin is normally secreted from renal proximal tubular cells in response to anemia or hypoxia and it then stimulates erythroid precursors
- Epo is a recombinant erythropoietin glycoprotein given IV or SC
- Uses: anemia of chronic renal failure, HIV pts on zidovudine, pts on chemo (non-myeloid malignancies), anemic pts having surgery
- Hb levels to 10-12
- Adverse effects on HTN and CV events
Myeloid Growth Factors
- Granulocyte (G-) and Granulocyte macrophage (GM-) CSF are secreted from a variety of cell types in response to inflammation and antigenic stimulation
- Act on Myeloid precursors to stimulate the production of granulocytes
Filgrastim
- activity is restricted to neutrophils
- Reduces risk of infx in pts with non-myeloid cancers undergoing myelosuppressive chemotherapy
- Severe chronic neutropenia
- AE = bone pain
Oprelvekin
- Recombinant version of IL-11 (thrombopoietic growth factors) given SC
- Stimulate proliferation and maturation of megakaryocyte progenitor cells
- Minimizes thrombocytopenia and reduces the need fro platelet transfusions in pts with non-myeloid cancers undergoing myelosuppressive chemo
- Takes 5-9 days after treatment to begin working
- AE: Fluid retention, peripheral edema, and cardiac arrhythmias
Characteristics of neoplastic cells relevant to Pharm
- Self: Evades immune recognition and limits targets
- Persistent proliferation: Traditionally only selective target
- Self-Sufficient growth signaling: New selective drug target
- Evasion of apoptosis: drug resistance
- Genomic instability: tumor cell heterogeneity
- Invasive growth and metastasis:
- Angiogenesis: need for a new blood supply
- Cancer stem cells: low rate of proliferation and high degree of resistance (wrong target)
Transition through cell cycle
- Controlled by cyclins which activate cyclin dependent kinases
- Checkpoints monitor DNA integrity (p53 at G1/S) mutation or loss of p53 leads to continued progression through cycle even if DNA damage exists
Antineoplastic Classification
- Classified by which phase of the cycle they target
- Phase-specific drugs: a particular phase of cycle (prolonged infusions or multiple doses at short intervals)
- Phase Non-specific Drugs: require entry in to cell cycle by can be given at any time (bolus)
- Growth fraction: ration of proliferating cells to cells in G0
Log cell-kill model
- Constant fraction of cells is killed regardless of the number of malignant cells actually present
- Same dose reduces tumor burden from 100-10 as 5-2 (rationale for multiple cycles of chemo)
Gompertzian model
- Growth fraction of solid tumors is not constant but declines exponentially with a peak at 37%
- Growth declines as tumor outgrows blood supply and some cells exit the growth cycle making them resistant to chemo
Alkylating Agents
- Electrophiles that transfer alkyl groups to neutrophilic sites on DNA
- Bis-alkylation leads to intra or inter strand cross linking w/ associated protein
- Mechanism of action is cell cycle non-specific -> miscoding, scission of DNA and inhibition of DNA repair, but lethality depends on function p53 and intact apoptotic pathway.
- Resistance: Inactivation of drug by GSH
Nitrogen Mustards
- Alkylating agents
- Cyclophosphamide (oral not vesicant) & Mechlorethamine (IV and vesicant)
- Cyclophosphamide: prodrug –> 4-OH in liver
- Particularly active against CLL
- Toxic against bone marrow gi and liver (mild) but acrolein is cytotoxic to bladder –> hemorrhagic cystitis but prevented w/ hydration and Mesna (SH-donor)
Nitrosoureas
- Alkylating agents
- Carmustine (BCNU)
- similar to mustards but lipophilic and able to cross bbb
- carbamoylation of Lys residues on proteins (interfere w/ DNA repair) makes them non-cross resistant w/ other alkylating agents
- Interstitial lung disease
Platinum analogs
- Alkylating agents
- Cisplatin
- Inorganic metal complexes
- Forms intrastrand cross links between 2 guanine residues
- Toxicity: Administered by IV infusions over 8 hrs w/ hydration to prevent
- Immediate: severe nausea vomiting and anaphylaxis
- Delayed: nephrotoxicity and electrolyte distrubances administer with AMIFOSTINE an SH donor activated by alk phos in kidneys
- peripheral neuropathy and ototoxicity
Antimetabolities
- Take advantage of requirements of cancer cells for folate intermediates, purine, and pyrimidines essential for DNA or RNA synth
- Agents resemble natural metabolites and inhibit synth enzymes or become incorporated in DNA and interfere with replication
- S-phase
- Not carcinogenic bu teratogenic
Antifolates
-Methotrexate
-Folic acid analog that is potent and non-selective inhibitor of DHFR
-Transported to cells by the reduced folate transporter but require intrathecal injection for CNS
-Metabolized to polyglutamates and retained in Cancer cells
-Inhibits conversion of DHF –> THF and blocks de novo purine synthesis
-Resistance: decreased uptake via reduced folate transporter, decreased conversion to polyglut., Amplification or mutation of DHFR gene that overcomes inhibition or decreases affinity to MTX
Toxicity: Leucovorin (fully reduced 5-formyl THF) is given 24-36 hrs after admin to rescue BM and GI w/ high doses of MTX
Fluoropyrimidine analogs 5-FU
- Metabolized to FdUMP and inhibits thymidylate synthatase by forming a complex w/ TS and MTHF
- Metabolized FdUTP FUTP and incorporated into DNA and RNA
- Co-administered with Leucovorin which stabilizes complex (Colon cancer)
- Synergistic with MTX b/c MTX enhances the activation of 5-FU by blocking purine synthesis
Fluoropyrimidine analogs Capecitabine
- Capecitabine
- Orally active prodrug of 5-FU w/ reduced toxicity b/c first 2 steps occur in liver and 3rd step occurs in tumor where thymidine phosphorylase is highly expressed
- Specific toxicity: Acral erythema (hand-foot syndrome)
- Neurotoxicity: delayed CNS degeneration
- 5-8% of cancer patients lack dihydropyrimidine dehydrogenase –> inability to metabolize 5-FU which leads to severe toxicities
- Resistance: decreased levels of activation enzymes or mutated TS w lower binding affinity for 5-FU
Deoxycytidine Analogs (Cytarabine)
- Cytarabine (Ara-C)
- Converted to 5-nucleotide ara-CTP
- Competitive inhibitor of DNA polymerase that inhibits DNA synthesis and repair by causing chain termination
- AML
- Resistance: Decreased conversion to ara-CTP
- Hand foot syndrome
Purine Agonists (mercaptopurine)
- Mercaptopurine
- metabolized by hypoxanthine-guanine phosphoribosyl transferase to thioinosine monophosphate
- T-IMP inhibits monophosphate dehydrogenase blocks conversion of IMP to GMP and formation of AMP
- Resistance: mutation in HGPRT
- A.L.L
- Toxicity: Inactivated by XO which is inhibited by allopurinol frequently give for tumor lysis syndrome
- Hepatotoxicity (cholestatic jaundice)
- Pt’s with thiopurine methyltransferase deficiency have increased risk of myelosuppression and GI toxicity
Purine Agonists (hydroxyurea)
- S-phase specific
- Inhibits ribonucleotide reductase preventing conversion of ribonucleotides to deoxyribonucleotides
- Cell cycle arrest at G1/S (highly sensitive to radiation)
- Used in sickle cell anemia, and myeloproliferative disorders
Antitumor antibiotics (Doxorubicin)
- Planar molecule that can intercalate into the DNA helix
- Inhibit topoisomerase II, Block DNA/RNA synthesis, generation of free radicals
- Acute transient arrhythmias usually asymptomatic
- Dose dependent CHF due to Fe-dependent production of free radicals (co-admin with dexrazoxane
Antitumor antibiotics (Bleomycin)
- mixture of small glycopeptides each w/ DNA binding domain and fe chelating domain at opposite ends
- MOA: G2 specific
- Chelates iron to form a heme like ring
- Binds to DNA and produces Fe2 induced oxidative damage that results in strand breaks and inhibition of DNA synthesis
- Resistance: Bleomycin hydrolase overexpression in cancer cells inactivates the drug
- Toxicity:
- Pneumonitis –> severe pulmonary fibrosis
- Anaphylactic rxn
Antitumor antibiotics (Actinomycin D)
- Planar molecule that intercalates DNA
- Distorts DNA structure resulting in inhibition of RNA polymerase
Vinca Alkaloids (vinblastine and vincristine)
- Mitotic inhibitors
- M-phase specific
- MOA:
- Inhibit polymerization of tubular by binding to (+) cap
- Disrupts assembly of microtubules and causes random distribution of chromosomes
- mitotic arrest in metaphase
- Doesn’t cross BBB
- Specific toxicity:
- Vincristine: periph. sens. neurop.
- Vinblastine: myelosuppressive
- BOTH DEADLY W/ INTRATHECAL ADMIN
Taxanes (paclitaxel)
- Mitotic inhibitor
- MOA: G2 and M phase specific
- Inhibits depolymerization and enhances polymerization (GTP independent) binds to beta subunit
- inhibits mitosis and cell division
- prevents restenosis in CA stents
- Toxicity:
- periph. neurop.
- Hypersenstivity run from vehicle
Camptothecins (irinotecan)
Topoisomerase inhibitors
- MOA: inhibits topoisomerase I prevents religation of cleaved strand (S-Phase specific)
- UGT1A1*28 increases toxicity risk
Epipodophyllotoxins (etoposide)
Topoisomerase inhibitors
-MOA: inhibits mammalian topo II prevents religation (s and G2 specific)
BCG vaccine
- inflamm response when administered in bladder –> regression of urothelial tumors
- Uses carcinoma bladder insitu
Asparaginase
-Enzyme that converts asparagine to aspartic acid
-Lowers circulating levels of asparagine –> protein synthesis inhibition in ALL cells (not normal cells)
-Acts in G1
Specific toxicities
-hypersensitivity rxn
-coagulopathy decreases synth of coag factors in liver
-CNS depression (confusion –> coma)
NO MYELOSUPPRESSION OR ALOPECIA but SEVERE NAUSEA AND VOMITTING
imatinib (gleevec)
- Small molecule tyrosine kinase inhibitor
- Competitive inhibitor of TKs (BRC-ABL) suppresses proliferation and promotes apoptosis of CML
- USES: Ph+ CML and c-kit+ GI tumors
- Adverse effects: edema with complications (CHF), rash, hepatotoxicity, penias, nausea, vomiting, diarrhea, hemorrhage
- CYP3A4
Erlotinib
- Small molecule tyrosine kinase inhibitor
- MOA: competitive inhibit of EGFR RTK –> decrease down stream signaling of RAS
- USE: locally advanced or metastatic non-small cell lung and pancreatic cancers
- AE: acneiform rash, diarrhea, nausea, vomiting, hepatotoxicity, ILD
- CYP3A4
Trastuzumab
- Monoclonal antibodies
- Binds extracell HER2 and inhibits cell proliferation and promotes ab mediated death
- Adjuvant for HER2+ breast CA
- Toxicity:
- Cardiac: LV dysfunction
- Infusion rxn and hypersensitivity
- NO MYELOSUPPRESSION OF ALOPECIA
Cetuximab
- Monoclonal antibodies
- Competitive EGFR inhibitor (bind extracell domain) blocks downstream phosphor and prevents cell prolif and promotes apop
- EGFR+ and wild type K-RAS+ metastatic colon CA
- AE: Infusion RXN despite prophylactic anti histamines, acneiform rash and hypomagnesemia ILD
