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ANTICANCER DRUGS &IMMUNOMODULATORS

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“CANCER”

Refers to a Malignant neoplasm (New growth)

Cancer cells can manifest:

• Uncontrolled Proliferation.• Loss of function due to lack of ability to differentiate.• Invasiveness.• The ability to metastasize.

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• Cancer arises as a result of a series of genetic changes as well as life style

• in the cell, the main genetic lesions being:

• Inactivation of tumor suppressor genes.• The activation of oncogenes.

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TREATING CANCER

Treatment methods• Surgery• Radiation• Chemotherapy (drugs)

• Different cancers respond to different treatments.

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Antineoplastic drugs

• Are cytotoxic not tumoricidal • Only kill cells during mitosis, and• Not all cancer cells are dividing at the same time.

SUCCESS DEPENDS ON: • Stage of cancer at time of diagnosis • Type of cancer • Development of drug resistance • Overall health of patient.

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Problems with Chemotherapy

Toxicity to normal cells• Dose limiting• We don’t have cancer specific drugsHigh growth fraction human cells affected• Bone marrow• GIT epithelium• Hair follicles

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Problems with Chemotherapy

• Goal of treatment is a “CURE” REQUIRES 100% KILL RATE

• Solid tumors respond poorly• Drug resistance• Heterogeneity of cancer cells• Limited drug access to tumor cells

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THERAPEUTIC STRATEGIES

COMBINATION THERAPY• Attack diff. mechanisms• Different molecular sites• Different toxicities• Suppress drug resistanceOPTIMIZING DOSAGE SCHEDULES REGIONAL DRUG DELIVERY• Intrathecal, IV etc.

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• Log kill• Chemotherapeutic agents follow first order kinetics• A given dose of a drug destroys a constant fraction of cells.• 10 to power of nine leukemic cells present and treatment

gives 99.999 percent kill, then o.oo1 percent of 10 to power of 9 cells would remain ie10 power of 4. This gives a five-log kill.

• At this point, the patient appears asymptomatic (in remission) and additional treatment is required to totally eradicate the leukemic cell population.

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Benefits of chemotherapy

• CURE• PALLIATION• PROLONGATION OF USEFUL LIFE

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CELL GROWTH CYCLE

5 DISTINCT PHASES OF MITOSIS

1. G0 - Resting - no mitosis 2. G1 - Post mitotic - first growth 3. S - DNA synthesis phase (replication) 4. G2 - Premitotic - second growth 5. M - Mitosis phase (cell divides) GENERATION TIME - one complete cycle different

in all tumors, from hours to days

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R

• Tumor Suppressor Genes -ve (p53)• Growth Factors Oncogenes +ve

S DNA Synthesis

G2

Premitotic Interval

MPROPHASEMETAPHASEANAPHASETELOPHASE

MITOSIS

G0G1

S PHASE SPECIFIC Cytosine Arbinoside Hydroxyurea S PHASE SPECIFIC SELF LIMITING6-MercaptpurineMethotrexate.

M PHASE

SPECIFICvincristinevinblastinepaclitaxel

PHASE NONSPECIFICalkylating agents, cis -platinumnitrosoureas, dacarbazineantibioticsprocarbazine

G0

Differentiation

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PENTOSTATIN

Inhibits adenosine Deaminase

PALA

Inhibits Pyrimidine Biosynthesis

Purinesynthesis

Pyrimidine synthesis

Ribonucleotides

Deoxyribonucleotides

DNA

HYDROXYUREA

InhibitRibonucleotide

Reductase

6-MERCAPTOPURINE 6-THIOGAUNINE

Inhibit Purine ring biosynthesisInhibit Nucleotide interconversions

5-FLOUROURACIL

Inhibit TMPSynthesis

METHOTREXATE

Inhibit dihydrofolatereduction, blocksTMP and Purinesynthesis

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DNA

RNA(Transfer, messenger, ribosomal)

CYTARABINE FLUDARABINE2-CHLORODEOXY ADENOSINE

Inhibit DNA Synthesis

ALKYLATING AGENTSMITOMYCETINCISPLATINPROCARBAZINEDACARBAZINE

Form adducts w/ DNA

BLEOMYCINETOPOSIDE

Damage DNA andPrevent repair

DACTINOMYCINEDAUNORUBICINDOXORUBICINMITOXANTRONE

Intercalate with DNAInhibit DNA, RNA

synthesis

PROTEINS

Enzymes Microtubules

A-ASPARAGINASEDeaminate asparagine

Inhibits proteinsynthesis

PACLITAXELVINCA ALKALOIDSNAVELBINE

Inhibit function ofMicrotubules

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ANTINEOPLASTIC DRUGS

ADVERSE EFFECTS:

• cytotoxic to all fast growing cells • Hair follicles• GI tract mucosa• Bone marrow suppression (BMS) causing anemia and leukopenia • All are CI in pregnancy • Most are nephro - hepato- and ototoxic • Extravasation of IV can result in loss of limb

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Antineoplastic Agents

ADVERSE EFFECTS: (Contd) • All have a BMS and emetic index • All have wide interaction with other drugs. • Special training required for nursing

Treatment of bone marrow suppression• Neutropenia: filgastrim• Thrombocytopenia: platelet transfusion• Anemia: erythropoietin, packed red blood cell

transfusion

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DEFINITIONS:

• GROWTH FRACTION % of cells in mitosis at any given time

• LEUCOVORIN RESCUE - use of leucovorin to reverse methotrexate-induced toxicity

• MITOTIC INDEXnumber of cells per unit undergoing mitosis during a given time

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ANTINEOPLASTIC AGENTS 2 MAIN GROUPS OF AGENTS:

CELL CYCLE - NONSPECIFIC (CCNS) ALKYLATING AGENTS cytotoxic in any phase of cell cycle effective against slowly growing tumors & fast growing

tumorsCYTOTOXIC ANTIBIOTICS (some are CCNS)

CELL CYCLE - SPECIFIC (CCS) ANTIMETABOLITES - cytotoxic in S phase MITOTIC INHIBITORS - cytotoxic in M phase effective against rapidly growing tumors

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Alkylating Agents

• Carmustine• Lomustine• Cyclophosphamide• Ifosfamide• Mechlorethamine• Streptozotocin• Mitomycetin• Dacarbazine• Chlorambucil

mechlorethamine

• MOA: ALKYLATES THE N7 nitrogen of a guanine residue in one or both strands of DNA molecule. It leads to:

• Cross linkage of guanine residues in the DNA chains thus facilitating strand break

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ALKYLATING AGENTSNITROGEN MUSTARDS CCNS killing ability Mechlorethamine is the prototypical agent USES: Hodgkin’s disease & lymphomas. leukemias, CANCERS OF solid tumors lung, breast, ovary, testes, brain, bladder,

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ALKYLATING AGENTS

SELECTED AGENTS:

•Mechlorethamine IV only (adult use only) •Carmustine IV, adult only, can cross blood-brain barrier, therefore used to treat brain lesions

• Cyclophosphamide

• IV and PO, adults and pediatric use • USES: burkitt lymphoma, breast cancer, • Other uses: nephrotic syndrome, intractable rheumatoid

arthritis• SE: BMS esp leukocytosis, hemorrhagic cystitis which

can lead to fibrosis of the bladder(due to acrolein), alopecia, nausea, diarrhea

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Cyclophosphamide (Inactive)

Hepatic Cytochrome P450 0xidase

4-Hydroxycyclophosphamide Aldophosphamide

Enzymatic

Non enzymatic

Hepatic aldehyde oxidase

4-Ketocyclophosphamide (Inactive).

Acrolein Cytotoxic Phosphoramide Mustard Cytotoxic

Carboxyphosphamide (Inactive).

Responsible for unwanted effects

• Melphalan• Chlorambucil• Busulfan • USES: • Melphalan: multiple myeloma• Chlorambucil : chronic lymphocytic leukemia• Busulfan: chronic granulocytic leukemia• SE: Myelosuppression

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Antimetabolites

• Cytarabine• Fludarabine• 5-Fluorouracil• 6-Mercaptopurine• Methotrexate• 6-Thioguanine• Pentostatin• 2-Chlorodeoxy Adenosine• Capecitabine• Gemcitabine

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ANTIMETABOLITES

ACTIONS: •Antagonism of folate (Methotrexate) •Antagonism to Purines, and Pyrimidines needed for synthesis of nucleic acids -•Stops cell replication

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• USES: • Solid tumors • (breast, lung, liver, brain, colon. Stomach, pancreas) • Lymphomas, leukemias. • Some agents also immunosuppressive, • Useful in treating immune-mediated diseases

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ANTIMETABOLITES

SELECTED AGENTS: (FOLIC ACID ANALOG)• METHOTREXATE • Folic acid antagonist • PO & IM, adult and pediatric use • Also used to treat immune-mediated diseases, • Used in combination with Misoprostol for therapeutic abortion • Causes profound anemia (folate depletion) • Therefore leucovorin “rescue” often used to counteract

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ANTIMETABOLITES SELECTED AGENTS: •PYRIMIDINE CYTOSINE ANALOG -•CYTARABINE -Pyrimidine antagonist -IV and intrathecal (within spinal canal)SE: VOMITING, MYELOSUPPRESSION

Antimetabolites • SELECTED AGENTS: • PURINE, HYPOXATHINE ANALOG

• 6- MERCAPTOPURINE (6-MP) • - Purine antagonist • - PO only, adult and pediatric use • USES: remission of ALL, crohn disease• Drug interaction btw 6-MP and

allopurinol( therefore dose of 6-Mp have to be decreased in these patients to avoid its accum

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• 5 fluorouracil• Pyrimidine analog• Interferes with conversion of

deoxyuridylic acid to thymidylic acid (thymineless death)

• Severe gi toxicity• Dermopathy— erythematous

desquamation of palms and soles --hand foot syndrome

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Mitotic Inhibitors

Also called Microtubule inhibitors• Vincristine• Vinblastine• Paclitaxel• Navelbine

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MITOTIC INHIBITORS

ACTIONS: Plant alkaloids (periwinkle, yew tree, mandrake plant, etc.) Bind to and disrupt mitotic spindles

USES: Lymphomas (Hodgkin’s and non-Hodgkin’s),Neuroblastoma Kaposi’s sarcoma,Solid tumors (breast, testicular, etc.)

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MITOTIC INHIBITORS

SELECTED AGENTS: PACLITAZEL MOA: Hyperstabilize polymerized microtubule so that mitotic spindle cannot break down(no anaphase) IV only, adult use only Good drug for ovary and breast caSE: myelosuppression and hypersensitivity

• VINCRISTINE AND VINBLASTINE

• IV only, adult and pediatric use

• USES: WILMS’ TUMOR, CHORIOCARCINOMA, HODGKIN’S LYMPHOMA

• MOA: Bind to tubulin and block polymerization of microtubules so that mitotic spindle do not form

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• Adverse effects• Severe vesicant

• Must be careful of IV equipment to avoid slough • Vinblastine – potent myelosuppressant• Vincristine - Neurotoxicity (peripheral neuritis)

• sensory neuropathy Severe paresthesias, loss of reflexes, ataxia, and muscle wasting

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• MOPP REGIMEN• M—Mechlorethamine• O---Oncovin (vincristne)• P---Purinethol• P---Procarbazine• Mainly in the treatment of lymphomas

• POMP REGIMEN• P- prednisone• O- oncovin(vincristine)• M- methotrexate• P- purinethol (mercaptopurine)• Used in the treatment of acute lymphocytic leukemias

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Antibiotics

• Bleomycin• Dactinomycin• Daunorubicin• Doxorubicin• Idarubicin• Plicamycin• Mitoxantrone

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CYTOTOXIC ANTIBIOTICS ACTIONS: • Source: Streptomyces mold - work by intercalation (insertion of drug molecule between the 2 DNA strands leading to disruption of DNA function • Kill some bacteria and viruses but are too toxic to use for infections IV extravasation constant danger ! USES: wide variety of solid tumors, mostly used in combination with other agents

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• DACTINOMYCIN• FIRST ANTIBIOTIC TO BE USED FOR CHEMOTHERAPY• USED IN COMBINATION WITH VINCRISTINE FOR WILMS

TUMOR• WITH MTX FOR CHORIOCARCINOMA• MOA; intercalates in the minor groove forming a stable

dactinomycin-DNA complex which will inhibit DNA DEPENDANT RNA POLYMERASE function → inhibition of DNA synthesis

• Also inhibits the ligase function of topoisomerase-II → strand break→DNA syn

• SE: BONE MARROW DEPRESSION , IMMUNOSUPPRESSION.

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CYTOTOXIC ANTIBIOTICS

SELECTED AGENTS:

DOXORUBICIN IV only, adult use only BLEOMYCIN IM, IV, SC, adult use only very toxic agents !!!

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• DOXORUBICIN & DAUNORUBICIN• ANTHRACYLCLINE ANTIBIOTICS• DOXORUBICIN IS HYDROXYLATED ANALOG OF

DAUNORUBICIN• SARCOMA, CARCINOMA OF LUNG, BREAST,• ACUTE LEUKEMIAS• MOA: Intercalates with DNA, generaation of free

radical →inhibition of DNA synthesis• SE: CARDIOTOXIC, alopecia, skin pigmentation, bone

marrow suppression, GIT disturbance

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• BLEOMYCIN• MIXTURE OF DIFFERENT COPPER CHELATED

GLYCOPEPTIDES• CELL CYCLE SPECIFIC.CELLS ACUMULATE IN THE G2

PHASE• MOA: complexes with Fe and oxygen forming free radicals

that results in DNA strand break• TESTICULAR TUMORS• WITH VINBLASTINE AND CISPLATIN 100% RESPONSE

RATE• SE: PULMONARY TOXICITY

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Others• Asparaginase• Cisplatin• Carboplatin• Etoposide• Hydroxyurea• Interferons• Procarbazine• Altretamine (Hexalen)• Topotecan• Trastuzumab• Rituximab

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MISCELLANEOUS ANTINEOPLASTICSVarious actions,Both CCNS and CCS Used in combinations with other agents

SELECTED AGENTS: •Cisplatin –Platinum coordination complex. nephrotoxic , ototoxic IV, adult and pediatric use•ALTRETAMINE (Hexalen) • PO only, adult use only, primarily used to treat ovarian cancer •ASPARAGINASE – hydrolyzes asparagine needed for growth of cancer cell• IV only, adult and pediatric use •HYDROXYUREA PO only, adult use only

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Steroid hormones and their antagonists• Tumors which are steroid hormone –sensitive may be

either • Hormone responsive• Hormone dependant• Both• Goal of treatment: hormone treatment of responsive

tumors usually is only palliative

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Steroid Hormones & Antagonists

1. Adrenocortical Suppressant:

Mitotane, Aminoglutethimide.

2.Adrenocortical Steroids - Prednisone

3.Progestins:

Hydroxyprogesterone

Medroprogestrone, Megesterol acetate.

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4.Estrogens: DES, Ethinylesterdiol

5.Antiestrogens: Tamoxifen & Raloxifene

6.Antiandrogens: Flutamide

7.Gonadotropin Releasing Hormone Analog: Leuprolide

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• Prednisone• Potent anti-inflammatory corticosteroid with less

mineralocoticoid activity than cortisol• Used to induce remissions in acute lymphocytic

leukemia and in treatment of both hodgkins and nonhodgkins lymphoma.

• Adv effects- cataracts, glaucoma, hyperglycemia, osteoporosis, mood swings

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• Tamoxifen SERM• Estrogen antagonist• First line therapy for estrogen receptor positive breast cancer• Binds to estrogen receptors• Leading to Depletion of estrogen receptors• Not related to any specific cell phase.• SE: hot flashes, nausea, vaginal bleeding, discharge,

thromboembolism, vision problems,

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• Leuprolide and goserilin• Analogs of gnrh. As gnrh agonists they occupy gnrh

receptor in the pituitary which leads to its desensitization and consequently inhibition of release of fsh and LH.

• response to leuprolide in prostatic carcinoma is equivalent to orchiectomy.

• Sustained release preparation, subcutaneous depot intramuscular injection.

Aromatase inhibitors

• Aromatase is responsible for extra-adrenal synthesis of estrogen from androstenedione which takes place in liver, fat, muscle, skin and breast tissue including breast malignancies.

• SE: osteoporosis

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• Aminoglutethimide: metastatic breast cancer in postmenopausal women

• Anastrozole and letrozole: estrogen dependent breast cancer

• Exemestane

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• Monoclonal antibodies• Directed against specific targets• Created from b lymphocytes (from immunized mice)

fused with b lymphocyte tumor cells• Resulting hybrid cells can be individually cloned and each

clone will produce antibodies directed against a single antigen type.

• Recombinant tech can be used to create humanized antibodies.

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• Trastuzumab• Rituximab• Bevacizumab• cetuximab

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• Trastuzumab• In patients with metastatic breast cancer over expression of

trans membrane epidermal growth factor receptor protein—HER 2 is present

• Usually given with paclitaxel can cause regression of cancer and metastases.

• MOA: works by down regulation of HER2-receptor expression , via induction of antibody-dependent cytotoxicity, decrease in angiogenesis

• SE: Congestive heart failure esp when given with anthracycline

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• Rituximab• First monoclonal antibody to be approved for the treatment of

cancer.• Directed against cd20 antigen on the surface of normal and

malignant B lymphocytes• CD20 plays a role in the activation process for cell-cycle initiation

and differentiation• Use– post transplant lymphoma and in CLL, rheumatoid arthritis• Must be infused slowly due to occurrence of fatal adverse reactions• SE: hypotension, bronchospasm and angioedema, chills and fever

due to activation of complement which release ILs and TNF-α• Activation of TNF can result in reactivation of latent

TB.

• IMATINIB: • MOA: acts a signal transduction inhibitor used

specifically to inhibit tumor tyrosine kinase which associated with BCR-ABL fusion protein present in CML

• USES: Treatment of CML, GI stromal tumors• SE: fluid retention

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IMMUNOSUPPRESSIVE DRUGS

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Overview

• Immune system protects the body against harmful foreign molecules.

• However, in some instances, this good can result in serious problems e.g., in transplantation causing rejection

• Transplantation of organs and tissues has become routine due to improved surgical techniques and better tissue typing.

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Drugs available• Drugs now available more selectively inhibit rejection of

transplanted tissues while preventing the patient from becoming immunologically compromised.

• Earlier drugs cause patients to frequently succumb to infections due to suppression of antibody and cell-mediated immunity.

• Today’s approach alters lymphocyte function using drugs or antibodies against immune proteins(antigen).

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Strategies of treatment

• Agents that interfere with cytokine production or action e.g., ILs, TNF, IFN

• Some disrupts cell metabolism, preventing lymphocyte proliferation

• Mono-and-polyclonal antibodies block T-cell surface molecules e.g., cluster of differentiation cells (CD-cells)

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Selective inhibitors of cytokine production and function• Cytokines are soluble, antigen-nonspecific, signaling

proteins that bind to cell surface receptors on a variety of cells

• Cytokines include interleukins, interferons, tumor necrosis factors , transforming growth factors, colony stimulating factors.

• Example: IL2 stimulates proliferation of antigen primed Tcells.

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• Cyclosporine• Cyclic peptide composed of 11 amino acids• Extracted from a soil fungus

• MOA: diffuses into the T-cell, binds to a cyclophilin to form a complex that inhibits calcineurin→ ultimate inhibition of synthesis and release of cytokines including IL-2→ decrease number of T-lymphocytes → cell mediated immunity

• Preferentially suppresses cell mediated response, humoral immunity affected less.

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• USES: to prevent rejection of kidney, liver and cardiac transplants .

• Alternative to methotrexate in treatment of rheumatoid arthritis, recalcitrant psoriasis

• Can be given orally or iv.• Better to combine with glucocorticoid• Excreted through the bile/ urine• SE: Nephrotoxic, hepatotoxicity, glucose intolerance,

hirsutism, gum hyperplasia

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Tacrolimus (FK506)• Macrolide isolated from soil fungus• USES: Prevention of liver/renal transplants• Given with a glucocorticoid• Preferred over cyclosporine cos of its potency, decreased

episode of rejection and it requires lower doses of glucocorticoid→decrease in likelihood of steroid associated adverse effect

• MOA: same as cyclosporine but binds to a different immunophilin, FKBP-12

• Oral or iv.• Absorption < if taken with high fat food.

• SE: nephrotoxicity and neurotoxicity(tremor, seizures, hallucination), insulin dependent DM in blacks and Hispanics

• NO gum hyperplasia, hirsutism

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Sirolimus(SRL)

• Originally called rapamycin• Obtained from fermentations of soil mold• Equipotent to cyclosporine• Prevent renal transplant rejection• Given with cyclosporine and glucocorticoid to decrease

toxicity of the drugs

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• MOA; binds to same FK-Binding Protein just like tacrolimus, but instead of binding to calcineurine, it binds to mTOR(Mammalian protein of rapamycin)

• Thereby blocking the progression of activated T-cells from G1 to S phase of the cell cycle→inhibition of proliferation of T-cells

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• Pharmacokinetics: oral only• SE: HYPERLIPIDEMIA, hypertension, diarrhea• Increases nephrotoxicity of cyclosporine when given

together

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Immunosuppressive antimetabolites• Used in combination with glucocorticoids, cyclosporine and

tacrolimus• --Azathioprine• It is a prodrug that is converted first to 6mercaptopurine and then

to thionisinic acid→ inhibits purine synthesis required for cell division

• Lymphocytes are majorly affected• SE --Bone marrow suppression, nausea and vomiting• NOTE: care should be taken when administered along with

allopurinol

others• Mycophenolate mofetil: used in heart, kidney and liver

transplant because of its ability to prolong graft survival.• MOA: hydrolyzed to mycophenolic acid which functions as a

reversible uncompetitive inhibitor of IMP dehydrogenase → inhibition of de novo formation of GMP → inhibition of B and T lymphocytes of purines

• Given orally• SE: diarrhea, leukopenia, sepsis, infections &

lymphoma

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ANTIBODIES

• Prepared by immunization of rabbits/horses with human lymphoid cells producing a mixture of polyclonal antibiotics directed against a number of lymphocyte antigens

• Rationale: Prolongs graft survival•

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Muromonab-CD3 (OKT3)• Monoclonal antibody --hybridoma technology• Directed against glycoprotein CD3 antigen of human T-cells • Used for acute rejection of renal allografts, steroid-resistant

acute allograft rejection in cardiac and hepatic transplant patients.

• Binding to the CD3 protein results in disruption of T-lymphocyte function in immune response

• Circulating T-cells are depleted• T-cells usually return to normal within 48 hours of

discontinuation of therapy

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• Antibody administered iv.• SE: - cytokine release syndrome following the first

dose(mild flu-like illness to life-threatening shock-like reactions), anaphyllactoid reaction, CNS toxicity, ↑CMV infections

• Premedicate with methyl prednisolone, diphenhydramine & acetaminophen with regards to cytokine release syndrome

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adrenocortico steroids-

• Glucocorticoids first used for immunesuppression both in transplantation and in various autoimmune disorders

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• Prednisone, methylprednisolone commonly used for transplantation

• USE; to suppress graft rejection• Prednisone or prednisolone used for autoimmune diseases• Exact mechanism not known• T cells affected the most.• Lymphocycte population decreases• SE—diabetogenic, osteoporosis, cataracts, Glaucoma.• Efforts to reduce/remove steroids are on