Hematology pharmacology

2. Antiplatelet Agents
● Thienopyridine Derivatives (Clopidogrel and Ticlopidine)
● Clopidogrel and ticlopidine are thienopyridine-derived antiplatelet
medications that act via a mechanism other than that of aspirin.
Clopidogrel works by irreversibly inhibiting the binding of ADP to its
receptor on platelets, thereby reducing platelet aggregation.
● USES - stroke, coronary arter disease, and peripheral arterial
disease. It is also used to reduce thrombosis after cardiac stent
placement or in patients who cannot tolerate aspirin therapy.
● Side effects include bleeding, severe neutropenia, TTP, rashes, and
dyspepsia (ticlopidine is associated with a worse side effect profile
than clopidogrel).
● Contraindicated in patients with active bleeding.

3. ● Abciximab
● Abciximab is a monoclonal antibody
● platelet aggregation inhibitor by binding the GpIIb/GpIIIa
receptor on activated platelets.
● Used as an anticoagulant in acute coronary syndrome and
also to prevent restenosis after coronary angioplasty.
● Side effects include bleeding (GI bleed) and
thrombocytopenia.
● Contraindicated in patients with active bleeding, recent GI
bleed (within 6 weeks), or thrombocytopenia.

4. ● Phosphodiesterase III inhibitors (Cilostazol, Dipyrimadole)
● Stop clot formation by blocking the enzymes that normally inactivate cyclic AMP
(cAMP), leading to increased levels of cAMP in platelets.
● cAMP is an important mediator of platelet activity and increased levels lead to inhibition
of platelet Phosphodiesterase III inhibitors (Cilostazol, Dipyrimadole) aggregation.
● Also act as direct arterial vasodilators by inhibiting the cellular reuptake of adenosine,
leading to increased levels of extracellular adenosine. Increased adenosine levels then
act as a local vasodilator.
● Clinical uses include angina prophylaxis, intermittent claudication, prevention of stroke
or transient ischemic attack (when combined with aspirin).
● Side effects are related to its function as a vasodilator, including headache, nausea,
hypotension, palpitations (arrhythmias), GI upset, and thrombocytopenia.
● Contraindications include heart failure (especially New York Heart Association [NYHA]
class III and IV failure), tachycardia, and hypovolemia.

5. ● Thrombolytics
● Alteplase (tPA), Reteplase (rPA), Tenecteplase (TNKase), Streptokinase:
● Dissolve blood clots by a process referred to as thrombolysis.
● Catalyze the formation of endogenous plasmin (the protease that removes clots or
thrombi) from plasminogen.
● Plasmin cleaves fibrin as well as thrombin clots. You will see elevation of PT and PTT,
without any change in platelet count.
● Used for treatment of MI, ischemic stroke, or massive PE. Side effects include bleeding,
specifically hemorrhagic stroke.
● Contraindicated in patients with a history of hemorrhagic stroke, known intracranial
malignancy, known cerebral vascular lesion (arteriovenous malformation), recent ischemic
stroke (within last 3 months), known bleeding disorder or active bleeding, suspected aortic
dissection, or significant closed head/facial trauma (within 3 months).
● Relative contraindications include severe hypertension, recent major surgery, or pregnancy

6. Antineoplastics
● Antimetabolites
● Methotrexate (MTX
● Inhibits dihydrofolate reductase (DHFR) and prevents the regeneration of folate for
continued use in DNA synthesis.
● Not selective for tumor DHFR versus normal DHFR; therefore, it can affect the DNA
synthesis and cell growth of normal and tumor cells. However, it does have a greater toxic
effect in the DNA synthesis (S phase) of cells that are rapidly dividing.
● Used as an antineoplastic agent used with other chemotherapeutic agents to treat
leukemias, NHL, and other malignancies. It is also used as an immunosuppressant in the
treatment of rheumatoid arthritis.
● Methotrexate is used in the medical management of ectopic pregnancy.
● Side effects commonly include bone marrow suppression, liver damage, and neurotoxicity.
● Toxic effects can be diminished with the administration of leucovorin (folinic acid), which is
taken up in disproportionate amounts by normal cells (versus tumor cells).

7. ● 5-Fluorouracil (5-FU
● A pyrimidine analog that acts during the S phase of the cell cycle.
● 5-FU halts DNA and protein synthesis. 5-FU is an antimetabolite
that irreversibly inhibits thymidylate synthase, thereby blocking
the synthesis of thymidine.
● Used in the treatment of colon cancer and superficial tumors
(basal cell carcinoma).
● Side effects include myelosuppression, GI mucositis, and
photosensitivity.
● Side effects cannot be reversed by leucovorin.

8. ● Azathioprine and 6-Mercaptopurine (6-MP):
● A Prodrug that is nonenzymatically cleaved to create 6-MP. 6-MP
(analog of adenine) is an antimetabolite that works by inhibiting
many enzymes involved in de novo purine synthesis (S phase).
● Used for the treatment of leukemias and lymphomas. They are
also immunosuppressants used to treat certain autoimmune
disorders, including rheumatoid arthritis, SLE, and inflammatory
bowel disease.
● Side effects include bone marrow suppression, GI mucositis, and
liver damage. 6-MP is metabolized by xanthine oxidase and may
result in increased toxicity in patients taking allopurinol.

9. ● 6-Thioguanine (6-TG): 6-TG is a guanine analog antimetabolite that works
similarly to 6-MP.
● It blocks the synthesis of guanine nucleotides and results in the arrest of DNA
and RNA synthesis (S phase).
● Used in the treatment of acute leukemias and chronic myeloid leukemia.
● Side effects are similar to 6-MP except that it can be given with allopurinol.
● Cytarabine: Cytarabine is an S phase–specific antimetabolite (analog of
deoxycytidine, a deoxyribonucleoside resembles cytidine, with one oxygen
atom removed) that blocks DNA synthesis by incorporating itself into the
internucleotide linkages in DNA.
● Clinically it is used in the treatment of acute leukemias (AML, ALL) and in
lymphomas (induction therapy).
● Side effects include bone marrow suppression and GI mucositis.
●

10. ● Cladribine (2-CDA): Cladribine is a synthetic
purine analog that is used in the treatment of
hairy cell leukemia. It is an immunosuppressant
that inhibits DNA processing by cells. It is an
adenosine deaminase inhibitor.
● Clinically used for treatment of hairy cell
leukemia.
● Side effects include bone marrow suppression,
neurotoxicity, and renal toxicity.

11. Antitumor Antibiotics
● Dactinomycin
● Dactinomycin (actinomycin D) is an antibiotic used as a chemotherapy medication, which
disrupts the cell cycle by inhibiting transcription. It works by binding double-stranded DNA
and blocking elongation of the chain by RNA polymerase.
● Used to treat Wilms tumor in children (may be curative if combined with surgery and
radiation), rhabdomyosarcoma, Ewing sarcoma, and choriocarcinoma.
● Side effects include bone marrow suppression and GI mucositis.
● Doxorubicin
● Doxorubicin (Adriamycin), an antibiotic, is the A part of the ABVD chemotherapeutic
regimen. It works by intercalating within DNA to disrupt replication and transcription.
Doxorubicin inserts itself into DNA, leading to breaks in the chain.
● Clinically it is used in the treatment of multiple myeloma, leukemias, HL, sarcomas, and
solid tumors (breast, ovary, bladder, and lung).
● Side effects include significant cardiotoxicity (leading to dilated cardiomyopathy), bone
marrow suppression, and alopecia.

12. ● Bleomycin
● Bleomycin is a G2 phase–specific drug and is the B part of the ABVD
chemotherapeutic regimen. This agent is a mixture of glycoproteins
that produce free radicals on binding DNA.
● The free radicals create breaks in DNA, which accumulate and lead to
cell death.
● Clinically it is used in the treatment of HL, testicular carcinoma, and
squamous cell carcinomas.
● Side effects include skin changes (hyperpigmentation, ulcers,
alopecia) and life-threatening pulmonary fibrosis (pulmonary function
must be monitored).
● It produces minimal bone marrow suppression.

13. Alkylating Agents
● Cyclophosphamide and Ifosfamide
● Cyclophosphamide is an alkylating mustard agent.
● Exerts its effects by alkylating DNA (lethal to cells) and is most toxic to
rapidly dividing cells. It is the most commonly used alkylating agent.
● Cyclophosphamide is unique in that it can be administered orally.
● Both cyclophosphamide and ifosfamide require activation by the liver’s
P-450 system to function properly.
● Clinically it is used to treat NHL, breast carcinoma, and ovarian
carcinomas. It also acts as an immunosuppressant.
● Side effects include hemorrhagic cystitis, leading to bladder fibrosis (this
side effect is decreased by aggressive hydration and administration of
mesna) and myelosuppression.

14. ● Nitrosoureas
● Nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin) are
DNA alkylating agents used in chemotherapy.
●
Nitrosoureas are a subgroup of medications that work by alkylating the
cross-link strands of DNA to create breaks and inhibit its replication
(also leading to inhibition of RNA and protein synthesis).
● Medications must be metabolized into their active products.
● Carmustine (BCNU) and lomustine (CCNU) are two closely related
nitrosoureas that are highly lipophilic and readily cross the blood–brain
barrier, so they are used in the treatment of many brain tumors.
● Side effects include myelosuppression, renal toxicity, and pulmonary
fibrosis (after prolonged use).

15. ● Busulfan
● Busulfan is an alkyl sulfonate that acts as a nonspecific
alkylating agent. It acts similarly to other alkylating agents and
forms reactive intermediates that alkylate DNA bases (mostly
purines) leading to cross-linking of bases, abnormalities in base
pairing, and DNA strand breakage.
● Continues to play a role in the treatment of CML.
● Used in bone marrow transplantation (kills bone marrow cells in
preparation for the procedure).
● Side effects include pulmonary fibrosis (main side effect) and
hyperpigmentation.

16. Microtubule Inhibitors
● Vincristine and Vinblastine
● Vincristine (Oncovin) is a vinca alkaloid used as the O part of the MOPP
chemotherapeutic regimen. Vincristine is an M phase inhibitor of the cell cycle
and works by binding to tubulin, thereby preventing polymerization of
microtubules and spindle formation.
● Inhibition of microtubule formation leads to arrest of the cell cycle (at
metaphase) and stops mitosis.
● Vinblastine is a similar medication that is the V part of the ABVD
chemotherapeutic regimen.
● Used in the treatment of HL, leukemias, Wilms tumor, and choriocarcinomas.
● Side effects include peripheral neuropathy and constipation. Vincristine
causes minimal myelosuppression. Vinblastine, on the other hand, produces
significant myelosuppression.
●

17. ● Paclitaxel
● Paclitaxel (Taxol) is the first of the taxane family of chemotherapeutic
agents.
● M phase agent that prevents the breakdown of the mitotic spindle and
inhibits completion of anaphase.
● Acts by binding tubulin and promoting polymerization and stabilization of
microtubules (unlike the vinca alkaloids, which inhibit polymerization).
● Clinically it is used against ovarian carcinomas, breast cancer, squamous
cancers of the head and neck, and other cancers.
● Side effects include serious hypersensitivity reactions (e.g., dyspnea,
urticaria, hypotension), peripheral neuropathy, and bone marrow
suppression.

18. Topoisomerase inhibitors
● Podophyllotoxins (Etoposide and Teniposide)
● Etoposide and teniposide are podophyllotoxin-derived chemotherapeutic medications.
Members of the podophyllotoxin drug class are G2 phase specific and act by inhibiting
topoisomerase II.
● Form a three-part complex with DNA and topoisomerase II, leading to the inhibition of
topoisomerase II and an accumulation of breaks in the DNA (topoisomerase II normally reseals
double-stranded DNA breaks). The accumulation of breaks leads to degradation of DNA and
cell death.
● Etoposide and teniposide are used to treat lung and prostate carcinomas (small cell
carcinomas), testicular cancers, lymphoma (ALL), and AML.
● Side effects include bone marrow suppression and possible high rate of secondary leukemias
(in children treated with etoposide) with characteristic 11q23 translocation due to DNA breaks
induced by medication.
● Teniposide also inhibits topoisomerase II and is mainly used in the treatment of ALL.
● Side effects include severe myelosuppression, gastrointestinal toxicity, hypersensitivity
reactions, and alopecia.

19. ● Camptothecan Analogs (Irinotecan and Topotecan):
Irinotecan and topotecan are camptothecan derivatives
that act as topoisomerase I inhibitors.
● Topoisomerase I is an enzyme that changes DNA
structure by facilitating the relaxation of DNA supercoiling
during the process of replication and transcription.
● Clinical uses include colon cancer (Irinotecan), ovarian
cancer, and small cell lung cancer.
● Side effects include diarrhea and severe bone marrow
suppression.

20. Steroid Hormones and Their
Antagonists
● Prednisone
● Strong synthetic glucocorticoid that is the last P in the MOPP regimen.
● Has many actions on the body. Prednisone must be metabolized to prednisolone (active
form), after which it binds a cytosolic receptor and is transported into the nucleus,
activating specific corticosteroid response genes. Prednisone acts as an
antiinflammatory and immunosuppressant agent by blocking proliferation of activated T
cells and inhibits production of inflammatory mediators (also inhibits antibody
production). It may trigger apoptosis of immune cells, especially lymphocytes.
● Prednisone also produces neutrophilia (without bandemia) via demargination of
neutrophils in the circulation.
● Clinically it is used in the treatment of autoimmune diseases such as rheumatoid
arthritis and asthma but is also used in leukemias (CLL) and HLs.
● Side effects include hypercortisolism (Cushing syndrome), hyperglycemia, an increased
risk of infections, osteoporosis, muscle wasting, skin thinning, fat deposition, and
psychosis.

21. ●
Tamoxifen and Raloxifene
●
Tamoxifen is a selective estrogen receptor modulator (SERM) that acts primarily as an
antiestrogen but has
●
weak estrogenic activity.
●
Competes with estrogen for the estrogen receptor (tamoxifen is not effective in premenopausal
women because they produce enough estrogen to “out-compete” tamoxifen for the estrogen
receptor) and creates a nonproductive complex with its receptor, failing to induce estrogen-
responsive genes and RNA synthesis.
●
This results in suppression of growth in estrogen-responsive tissues.
●
Raloxifene (endometrial estrogen antagonist), a drug similar to tamoxifen, does not stimulate
endometrial growth and therefore does not increase the risk of endometrial cancer. It also
protects against osteoporosis.
●
Used in the treatment of estrogen receptor–positive breast cancer and to prevent osteoporosis
in postmenopausal women.
●
Side effects include nausea, vomiting, hot flashes, and increased risk of endometrial cancer
(tamoxifen only).

22. Other Agents
●
Cisplatin and Carboplatin
●
Platinum-containing compound that is a member of the platinum coordination complex class of
anticancer medications.
●
Cisplatin acts similarly to the alkylating agents; it enters the cell and creates interstrand and
intrastrand DNA crosslinks. These crosslinks result in DNA instability and cell death.
●
Clinically it is used in the treatment of testicular and lung carcinomas.
●
Side effects include significant nephrotoxicity, ototoxicity (cranial nerve [CN] VIII damage), and
mild myelosuppression.
●
Carboplatin is a similar agent, with less toxicity but greater bone marrow suppression.
●
Hydroxyurea
●
Hydroxyurea is an S phase–specific medication that inhibits DNA synthesis by blocking
ribonucleotide reductase, stopping the conversion of ribonucleotides to deoxyribonucleotides.
Hydroxyurea also acts by increasing the circulating levels of fetal hemoglobin.
●
Clinically it is used in the management of sickle cell anemia and various myeloid cancers (CML).
●
Side effects include bone marrow suppression, nausea, vomiting, and diarrhea (at high doses).

23. ● Trastuzumab
● Trastuzumab (Herceptin) is a monoclonal antibody that binds and inhibits the Erb-B2/HER-2 receptor
(a family of tyrosine kinases) expressed in some breast cancers. The HER-2 pathway promotes cell
survival, growth, and division.
● Clinically it is used in the treatment of metastatic breast cancer. Side effects include cardiomyopathy.
● Imatinib
● Monoclonal antibody that acts by binding and inhibiting the tyrosine kinase produced by the ABL and
C-KIT genes (there are a large number of tyrosine kinase enzymes in the body).
● Philadelphia chromosome in CML is produced by a fusion of the BCR-ABL genes creating a
constitutively active tyrosine kinase.
● C-KIT gene also produces a tyrosine kinase whose active site can be inhibited by imatinib.
Gastrointestinal stromal tumors often arise from mutations in the C-KIT gene.
● Clinically it is used as the first-line treatment for CML. It is also used to treat gastrointestinal stromal
tumors.
● Side effects include weight gain (most common), edema, bone marrow suppression, and possibly
congestive heart failure (CHF).

24. ● Rituximab
● An anti-CD20 monoclonal antibody that is used clinically to treat malignancies
(NHL, CLL) and autoimmune diseases (rheumatoid arthritis, ITP). Many B-cell
neoplasms are CD20+; however, CD20 is also found on normal B cells and
rituximab will destroy both.
● Side effects include fatal infusion reaction (deaths within 24 hours of infusion),
reactivation of hepatitis B and other viral infections ( JC virus infection leading
to PML), mucocutaneous reactions, and diarrhea.
● Erlotinib
● Erlotinib (Tarceva) is a reversible epidermal growth factor receptor (EGFR)
tyrosine kinase inhibitor used clinically to treat non–small cell lung cancer.
● Main side effect is a rash that resembles acne and primarily involves the face
as well as neck.

25. ● Bevacizumab (Avastin)
● Bevacizumab is a medication that inhibits angiogenesis (growth of new blood vessels). It is
a monoclonal antibody against vascular endothelial growth factor A (VEGF-A). VEGF-A is a
chemical signaler that promotes angiogenesis. Clinical uses include many solid tumors
such as colon cancer, renal cancer, ovarian cancer, lung cancer, and glioblastoma
multiforme.
● Side effects include GI perforations, impaired wound healing (because it blocks growth of
new blood vessels), and hemorrhage.
● Vemurafenib
● Vemurafenib is a B-Raf enzyme inhibitor that is used clinically for the treatment of
advanced melanoma. Most common side effects include arthralgia and rash.
● Cetuximab
● Cetuximab is an EGFR inhibitor used clinically to treat metastatic colon cancer (KRAS
wild-type), non–small cell lung cancer, as well as head and neck cancer.
● Most common side effect is acnelike rash.