| A | B |
|---|
| Ergocalciferol | Vitamin D2 |
| Cholecalciferol | Vitamin D3 |
| calcifediol | Product of 25-hydroxylation in liver |
| calcitriol | Product of 1-hydroxylation in kidney |
| DHT—dihydrotachysterol | Vitamin D analog no 1-OH needed for activation, does need liver 25-OH |
| 1a-Hydroxycholecalciferol | Vitamin D analog already has 1-OH group |
| Doxercalciferol (1-hydroxyvitamin D2) | Vitamin D analog, does need liver 25-OH |
| 22-oxacalcitriol MOA | suppressor of PTH gene expression, limited action on intestine and bone |
| 22-oxacalcitriol therapeutics | used in chronic renal failure, primary hyperparathyroidism |
| 22-oxacalcitriol indications | low affinity for serum binding protein leads to longer half-life than calcitriol |
| Estrogens | act on osteoblasts to decrease osteoclast recruitment and activation |
| Calcitonin | direct effect on osteoclast to decrease bone resorption |
| Calcitonin | decrease calcium and phosphate reabsorption in kidney |
| Glucocortiocoids | antagonize Vitamin D stimulated intestinal calcium absorption |
| stimulate renal calcium excretion | Glucocortiocoids |
| increase PTH stimulated bone resorption | Glucocortiocoids |
| block bone collagen synthesis | Glucocortiocoids |
| bisphosphonates indications | Non-hormonal Tx for osteoperosis |
| bisphosphonates MOA | retard formation and dissolution of hydroxyapatite imbibed by osteoclasts |
| close to pyrophosphate | bisphosphonates structure |
| bisphosphonate metabolism | metabolized into ATP analog, accumulates in osteoclasts |
| etidronate and tiludronate side effects | impairs cell function and viability, induces apoptosis |
| alendronate MOA | inhibition of protein prenylation important for osteoclast function |
| alendronate | less side effect of decrease bone mineralization |
| gastric irritation common with all bisphosphonates except | etidronate |
| zoledronate toxicity | some renal toxicity |
| Estrogens decrease | IL-6, IL-1, TNF-? |
| Estrogens increase | IGF-1, BMP-6, TGF-? |
| plicamycin | cytotoxic antibiotic that also decreases plasma [Ca++] by inhibiting bone resorption |
| gallium nitrate | inhibits bone resorption, renal toxicity |
| oral sodium phosphate | binds free ionized calcium, high risk procedure |
| edetate disodium (EDTA) | calcium chelator, high risk procedure |
| cinacalcet MOA | inhibits PTH secretion by lowering the[ Ca++] at which PTH secretion is suppressed |
| cinacalcet | calcimimetic |
| cinacalcet indications | 1' and 2' hyperparathyroidism and hypercalcemia of parathyroid carcinoma |
| thiazide diuretics | inhibit renal calcium stone formation by reducing renal calcium excretion |
| fluoride | both acute and chronic toxicities limit use |
| fluoride MOA | accumulates in bone and teeth may stabilize hydroxyapatite |
| Hypercalcemia tx | Bisphosphonates, calcitonin, plicamycin, gallium nitrate, phosphates, glucocorticoids |
| Osteoporosis tx | Bisphosphonates, calcitonin, vit D analogs, Ca+ supplements, thiazides, intermittent teriparatide |
| Paget’s disease tx | Calcitonin, bisphosphonates |
| Hypoparathyroidism tx | Vitamin D analogs |
| Hyperparathyroidism tx | oxacalcitriol, cinacalcet |
| renal osteodystrophy tx | Vitamin D analogs, phosphate binders |
| Cyclophosphamide – phase nonspecific Dynamics/Kinetics | (antitumor) by alkylation at guanine residues and acrolein |
| Cyclophosphamide- Dynamics/Kinetics | CYP2B > Aldophosphamide> to tumor cells where it cleaves spontaneously to phosphoramide mustard |
| Ifosfamide – phase nonspecific Dynamics/Kinetics | Analog of cyclophosphamide, also is activate by ring hydroxylation in liver |
| Mesna Dynamics/Kinetics | Redcd kidney to free thiol cpd > reacts with urotoxic metabolites (acrolein) |
| Vincristine – M phase specific Dynamics/Kinetics | Binds ?-tubulin inhibits ?/?polymerization w/o spindle arrest in metaphase |
| Filgrastim Dynamics/Kinetics | G-CSF – stimulates CFU-G to increase neutrophil production |
| Etoposide Dynamics/Kinetics | complex formed w/topoII and DNA prevents resealing; S and G2 phases |
| Dacarbazine- phase nonspecific Dynamics/Kinetics | metabolic activation in the liver - active form MTIC |
| Dacarbazine- phase nonspecific Dynamics/Kinetics | methylating agent inhibiting DNA, RNA and protein synthesis |
| Cisplatin Dynamics/Kinetics | Cl- replaced by H2O, yields cation that binds nucleophiles on DNA and proteins – cross links and breaks |
| Methotrexate – cell stage specific Dynamics/Kinetics | Inhibits DHFR as a folic acid analog, S phase, best with rapidly dividing cells |
| Bleomycin | accumulation of cells in G2 with chromosomal abnormalities |
| Bleomycin Dynamics/Kinetics | ROS damages deoxyribose of thymidylate; single and DSB in DNA, scission |
| Dactinomycin Dynamics/Kinetics | intercalcates between adjacent guanine-cytosine base; also causes single strand breaks |
| Doxorubicin ” Dynamics/Kinetics I | I.Intercalate with DNA (affecting transcription and replication) |
| Doxorubicin –Dynamics/Kinetics II | II. form a complex with topoII and DNA and inhibit relegation fo broken DNA à apoptosis |
| Doxorubicin –Dynamics/Kinetics III | III. Cause direct damage to DNA via oxygen radicals |
| Cyclophosphamide Toxicities | Hemorrhagic cysts with acrolein metabolite, myelosuppression, GI ulceration |
| Ifosfamide Toxicities | vs. cyclophosphamide causes worse platelet suppression, neurotoxicity, nephrotoxicity |
| Ifosfamide Toxicities | Severe urinary tract and CNS toxicity (without use of hydration and mesna) |
| Mesna Toxicities | N/V/D/ GI effects occasionally , bad taste in mouth is common occasional HA, fatigue, limb pain |
| Vincristine –Toxicities | Limited myelosuppression, neurotoxicity ( paresthesia DTR loss motor weakness), |
| Filgrastim Toxicities | skin reactions following subq, rare cutaneous necrotizing vasculitis ; |
| Filgrastim Toxicities | bone pain, mild to moderate splenomegaly with long term therapy |
| Etoposide Toxicities | Development of an acute nonlymphocytic leukemia with a chromosome 11 at 11q23 (MLL gene) |
| Dacarbazine- Toxicities | flu-like syndrome consisting of chills, fever, malaise, and myalgias |
| Cisplatin Toxicities | associated with development of AML usually 4 years or more after treatment |
| Cisplatin Toxicities | severe N/V (used often with antiemetic) Poor CNS penetration, nephrotoxicity, ototoxicity |
| Bleomycin Toxicities | Minimal myelo/immunosuprsn; unusual cutaneous effectsand pulmonary fibrosis |
| Dactinomycin – Toxicities | if given during chickenpox or herpeszoster, a fatal disease process can occur |
| Dactinomycin – Toxicities | Fever and fatigue common; severe myelosuppression |
| Red urine causes by drugs and metabolites common. –can use iron chelator to minimize cardiac toxicity | Doxorubicin –Toxicities |
| Doxorubicin –Toxicities | Dose related cardiomyopathy due to oxygen radical formation. |
| Cyclophosphamide –Therapeutics | Frequently combo w/ Methotrexate, Doxorubicin, and Fluorouracil; |
| Ifosfamide – Therapeutics | Widely used to treat pediatric and adult sarcomas |
| Mesna Therapeutics | Prophylactic tx for hemorrhagic cysts caused by cyclopphosphamide/ifosfamide |
| Vincristine –Therapeutics | CHOP regimen – cyclophosphamide, doxorubicin, prednisone (and vincristine) - IV |
| Filgrastim Therapeutics | With high dose chemotherapy, subcutaneous or IV injection |
| Etoposide Therapeutics | Oral/iv - **toxicity is increased in patients with decreased serum albumin ** |
| Dacarbazine- Therapeutics | IV administered |
| Cisplatin Therapeutics | IV administration; poor CNS penetration |
| Methotrexate –Therapeutics | nephrotoxicity and severe myelosuppression if drug is not excreted properly |
| Bleomycin Therapeutics | Parenterally , good combo drug because of little overlapping s/e |
| Dactinomycin –Therapeutics | IV |
| Doxorubicin – Therapeutics | Solid tumors. Usually given IV –CHOPS combo, |
| Cyclophosphamide – phase nonspecific | *Active p53 activity required for apoptosis of tumor cells ; |
| Cyclophosphamide – therapeutics | solid tumors and slow growing tumor choice, tx for bone sarcoma |
| Ifosfamide – phase nonspecific | Can administer with methylene blue to limit neurotoxicity |
| Vincristine – M phase specific resistance | Multidrug resistant tumor cells , ? tubulin mutations |
| Filgrastim | Produced in E.Coli, not glycosylated ( as in nature) and has extra N-terminal Met. |
| Etoposide resistance | Mutations of topo II, drug pumps, p53 = resistance, from extract of Mandrake |
| Dacarbazine- phase nonspecific | Resistance had been ascribed by removeal by AGT |
| Cisplatin | Aluminum inactivates, so impt in administration or mixture |
| Methotrexate – cell stage specific | High dose tx for osteosarcoma req coadmin of leucovorin to resupply folate to cells |
| Bleomycin | Fermentation products of Strep. Verticillus |
| Dactinomycin – “antibiotic” also called Actinomycin D | First iolsated from Streptomyces sp. |
| Doxorubicin – phase nonspecific – “antibiotic” | Derived from Strep. Peucetius . multidrug resistance is observed. |
| colchicine indications | Acute Gout |
| colchicine MOA | inhibits migration and phagocytic actions of granulocytesand PMN elaboration of inflammatory glycoprotein |
| colchicine side effects | nausea, vomiting, diarrhea, abdominal pain ; affects rapidly proliferating epithelial cells |
| allopurinol MOA | parent drug and metabolite alloxanthine inhibit xanthine oxidase, ¯ uric acid synthesis |
| inhibits metabolism of azathioprine, 6-mercaptopurine | allopurinol drug interaction: |
| tx for chronic gout with impaired renal function | allopurinol |
| probenecid MOA | uricosuric agent, inhibits uric acid renal tubular reabsorption |
| probenecid drug interactions | multiple due to blocking renal secretion |
| sulfinpyrazone indications | chronic gout tx with no anti-inflammatory or analgesic properties |
| probenecid | developed to inhibit renal tubular secretion of penicillin |
| colchicine side effects | interferes with mitotic spindle function |
| methotrexate at doses used for arthritis, effects probably due to: | inhibition of aminoimidazolecarboxamide ribonucleotide transformylase and thymidylate synthase |
| methotrexate anti-inflammatory actions include : | decrease leukocyte adhesion to endothelial cells |
| may inhibit transmethylation reactions of phospholipids and polyamines altering lymphocyte and neutrophil function/chemotaxis | methotrexate |
| methotrexate at doses used for arthritis, most common adverse effects: | nausea and mucosal ulcers, hepatotoxicity, monitor liver enzymes, after 5 years of use - -liver biopsy |
| alkylating agents/cross link DNA | cyclophosphamide, chloramabucil |
| toxic effects of cyclophosphamide, chloramabucil | bone marrow suppression, infertility, increased risk of infections and neoplasia |
| azathioprine MOA | converted to 6-mercaptopurine, inhibits de novo purine synthesis |
| azathioprine primary targets | T and B cells |
| any rapidly growing cell population | azathioprine toxicity |
| mycophenolate mofetil MOA | inhibits inosine monophosphate dehydrogenase de novo purine biosynthesis |
| interferes with leukocyte adhesion by inhibition of E- and P-selectin expression | mycophenolate mofetil MOA |
| T and B cell sensitive due to lack of salvage pathway | mycophenolate mofetil MOA |
| sulfasalazine MOA | acts by scavenging free radicals and as COX inhibitor and dihydrofolate reductase inhibitor |
| leflunomide | pro-drug; inhibits de novo ribonucleotide synthesis and triggers p53 translocation to nucleus arresting cells in G1 phase |
| leflunomide adverse effects | diarrhea as adverse effect in about 25% patients some liver toxicity |
| cyclosporine MOA | inhibits calineurin phosphatase activity, decrease transcription of cytokines in T-cells |
| somewhat selective effect on T-cells | cyclosporine indications |
| cyclosporin toxicity | Renal |
| chloroquine and hydroxychloroquine MOA | unclear MOA in arthritis, may decrease T-cell response to mitogens |
| chloroquine and hydroxychloroquine effects | decrease leukocyte chemotaxis, stabilize lysosomal membranes, trap free radicals, general decrease in DNA and RNA synthesis |
| chloroquine and hydroxychloroquine toxicity | fairly well tolerated |
| penicillamine MOA | unclear MOA in arthritis, may decrease DNA, collagen, and mucopolysaccharides synthesis |
| penicillamine | rarely used, toxic - - kidney damage, leukopenia, thrombocytopenia,and aplastic anemia |
| gold compounds toxicity: | lesions of skin and mucous membranes GI effects, renal toxicity, hematologic abnormalities |
| gold compounds indications: | use is in decline, second line drugs, use is in decline, second line drugs, |
| gold compounds MOA: | Unclear MOA, inhibit PMN and T-cell fxn may inhibit release of histamine, prostaglandins, leukotrienes |
| auranofin: | oral administration, lipid soluble |
| aurothiomalate, aurothioglucose | IM, water soluble |
| Anti- TNF-a drugs | Etanercept, Infliximab, Adalimumab |
| Anti- TNF-a drugs therapeutics | agents must given by injection, screen for latent or active tuberculosis |
| Anti- TNF-a drugs adverse effects | increase risk of macrophage dependent infections |
| Etanercept | recombinant fusion protein consisting of two soluble TNF receptor regions linked to Fc portion of human IgG |
| Infliximab | chimeric monoclonal antibody with variable murine region linked to constant human region specific against human TNF |
| Adalimumab | Recombinant human anti-TNF monoclonal antibody |
| Rituximab MOA | monoclonal antibody that targets CD20 (on B-cells) |
| Rituximab main use: | treatment of rheumatoid arthritis refractory to anti-TNF agents |
| Abatacept MOA | inhbt T-cell actvtn: binds CD80 (on APCs) prvnts interaction w/CD28 (on T cells) |
| Immunoadsorption apheresis | may down-regulate B-cell function by release of small amounts of immune complexes consisting of IgG and staph protein A |
| Immunoadsorption apheresis adverse effects: | fever, chills, joint pain and swelling,hypotension from IV, pulmonary emboli and sepsis |
| Immunoadsorption apheresis indications: | generally used in patients who have failed other therapies for rheumatoid arthritis |
| Dietary manipulation of rheumatoid arthritis inflammation : | Increase intake of eicosapentaenoic acid (EPA)(20:5, fish oil) |
| Cyclooxygenase-derived metabolites of EPA… | are much less potent mediators of inflammation than the corresponding metabolites of AA (prostaglandins) |
