PLANT ALKALOIDS Prof.Dr.,NASHAAT LOTFY PREPARED BY: ALIAA KHALID SALMA SADEK SHAIMAA ADEL MARWA SHAABAN MONA AHMED SUPERVISED BY: Prof.Dr.,NASHAAT LOTFY

INTRODUCTION Plant alkaloid chemotherapeutic agents, as the name suggests, are plant derivatives. They are cell-cycle specific chemotherapeutic agents. However, the phase affected is based on the drug used for the treatment.

CLASSIFICATION OF PLANT ALKALOIDS

PLANT ALKALOIDS,cont’d. VINCA ALKALOIDS TAXANES CAMPTOTHECINS PODOPHYLLOTOXIN

A)VINCA ALKALOIDS The vinca alkaloids are also called antimitotic or antimicrotubule agents, or mitotic inhibitors. Vinca alkaloids are derived from the periwinkle plant, Vinca rosea (Catharanthus roseus) Include vinblastine, vincristine, vindesine and vinorelbine(semi-synthetic)

VINCA ALKALOIDS,cont’d. MECHANISM OF ACTION: They are cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). They block the ability of tubulin to polymerize to form microtubules. The resulting dysfunctional spindle apparatus, frozen in metaphase, preventing chromosomal segregation and cell proliferation.

VINCA ALKALOIDS,cont’d. PHARMACOKINETICS: METHOD OF ADMINISTRARTION: For I.V use only through free flowing I.V. line to avoid extravasation FATAL if given by other routes. Intrathecal (IT) route is nearly always fatal and is a medical emergency. Exception: vinorelbine can be taken both orally and I.V. DILUTION: All can be diluted with either Glucose 5% or saline 0.9% except for vinblastine which is diluted only with saline 0.9%. Poorly & erratically absorbed by oral route, except for vinorelbine which is absorbed also orally. ABSORPTION Rapid and extensive binding to tissue DISTRIBUTION Hepatic cytochrome P-450 METABOLISM Primarily bilary/fecal Some renal excretion EXCRETION Doses must be modified in patients with impaired hepatic function or biliary obstruction.

VINCA ALKALOIDS,cont’d ORGAN SITE SIDE EFFECT Blood/bone marrow Leukopenia, granulocytopenia, anemia ,thrombocytopenia Neurological Variable Cardiovascular Hypertension, stroke, MI, Raynaud’s phenomenon esp. when combined with bleomycin. Dermatology/skin Extravasations, vesicant ,alopecia ,injection site pain ,phlebitis Gastrointestinal Constipation , nausea, vomiting , anorexia. Infection Pneumonia pulmonary Acute shortness of breath and bronchospasm dyspnea ,pulmonary edema Auditory Ototoxicity partial or total, temporary or permanent Miscellaneous Tumour lysis syndrome,tiredness, weakness, loss of fertility. CAUTION with opioid analgesics due to the risk of additive autonomic neuropathy which may result in severe constipation. CAUTION Patients with preexisting ischemic cardiovascular disease . A bowel regimen including high fiber diet and a stool softner should be initiated CAUTION Patients with preexisting pulmonary dysfunction CAUTION with other ototoxic medications such as platinum-containing antineoplastics,

VINCA ALKALOIDS,cont’d MECHANISM OF RESISTANCE: Resistant cells have been shown to have an enhanced efflux of vinca alkaloids via P-glycoprotein in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids. CONTRAINDICATIONS: Hypersensitivity to any component Pregnancy : Category D Breast feeding

COMPARISON

VINBLASTINE VINCRISTINE VINORELBINE VINDESINE INDICATION HALF-LIFE SYNONYMS VBL, VLB LCR, VCR, VX VRB,VRL,VNL, NVB DAVA, DVA, VDS TRADE NAMES Vilban® Velbe® Cytoblastin® Velbastine ® Oncovin® Vinacrine® Vincristine® Cytocristin® Navelbine® Eldisine ® INDICATION -Hodgkin’s and non-Hodgkin’s lymphoma -Testicular cancer -Kaposi’s sarcoma -Breast cancer -ALL &MM -Hodgkin’s and non- Hodgkin’s lymphoma -Chronic leukemias -Non-small cell lung cancer -Breast cancer. -Testicular cancers. -Ovarian cancers. -ALL & CML. -Lung carcinomas. -Colorectal cancer. HALF-LIFE 25 hrs 23-85 h adults: 28-44 h children: 14.7 h t½ α 3 minutes t½ β 0.8-1.7 hr t½ γ 20-24 hr DOSE & PROTOCOLS Hodgkin’s disease: (ABVD) 6 mg/m2 IV on day 1 and 15 Testicular cancer: (PVB) 0.15 mg/Kg IV on day 1 and 2 -Doses vary between 0.5 and 1.4 mg/m2. -The total individual dose should be limited to 2 mg to avoid neurotoxicity. Multiple myeloma (VAD) Continous infusion: 0.4 mg/day for 4 days. Leukemia [POMP] Orally: 60-80 mg/m2 once weekly for three weeks, MAXIMUM 160 mg once weekly By I.V. infusion: As a single agent: 30 mg/m2 weekly,given by intravenous infusion only over 6-10 minutes. As combination with cisplatin: 25mg/m2 weekly. Adults: 2-4 mg/m2 q1-2w 1.5 mg/m2/day x 5-7 days q3-4w Adriamycin Bleomycin Vinblastine Dacarbazine Vincristine Adriamycin Dexamethasone Cisplastin Vinblastin Bleomycin 6-MP(Purinethol), Oncovin, MTX Prednisone

-Autonomic neuropathy TOXICITY VINBLASTINE VINCRISTINE VINORELBINE VINDESINE NEUROTOXICITY: mostly mild parasthesia much less common and less severe than vincristine MYELOSUPPRESSION leukopenia; dose-related nadir 4-10 days CBC should be monitored. -1ry and dose-limiting. -reversible, but can persist for months after stopping therapy . -Peripheral neuropathy loss of deep tendon reflexes,parasthesi,pain in almost all patients -Autonomic neuropathy Resulting in constipation Central neuropathy headache, malaise, dizziness, seizures, depression, SIADH Mild and much less significant than with vinblastine less neurotoxicity than other vinca alaka GRANULOCYTOPENIA -dose-limiting. -nadirs occur between 7 -10 days -CBC with differentials should be performed& results reviewed prior to administering each dose -should not be administered to patients with granulocyte counts < 1,000 cells/mm3 Mostly severe -usually severe. - CBC with differentials with granulocyte counts < 1,000 cells/mm3 NEUROTOXICITY: Careful baseline neurologic evaluation should be performed before starting therapy and at the start of each cycle. Granulocytopenia :

DRUG-DRUG INTERACTIONS MANAGEMNET MECHANISM EFFECT AGENT -Avoid combination -Decrease dose & monitor for toxicity Inhibition of metabolism via CYP450 Toxicity Cyclosporin Erythromycin Cimetidine & Azole antifungals -Observe clinical response when starting or stopping carbamazepine Enhance metabolism via CYP450 Efficacy Carbamazepine Monitor phenytoin serum levels observe development of siezures. Decrease absorption &/or increase metabolism of phenytoin Efficacy of phenytoin Phenytoin Monitor for signs of reduction in digoxin efficacy. Decrease absorption Efficacy of digoxin Digoxin Use bronchodilators, corticosteroids and/or oxygen for symptomatic relief Unknown -Acute dyspnea& bronchospasm Mitomycin Monitor for signs and symptoms of neuropathy Additive effect Neurotoxicity Cisplatin Paclitaxel