Sketchy Pharm - Complete Sans Pix

• nucleosides consist of nitrogenous base, ribose, phosphate groups. Purine synthesis begins with phosphoribosyl pyrophosphate (PRPP) (synthesis continues! Pentagon pedestal being built with 3 P-shaped hammers). Metabolized to inosine monophosphate (IMP) (gargoyle imp), which is metabolized to AMP and GMP by separate pathways (gold gramps & grump statues respectively with purine haloes; “Pure As Gold”) Purine analog analogss • Azathioprine (AZA) & 6-mercaptopurine (6-MP) (Aza-merelda with purine earrings; captured gypsy) o AZA is converted to 6-MP, which must be activated by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) (high priest activated captive). Blocks synthesis of IMP (knocking over gargoyle imp) → halting DNA & RNA synthesis o Cell cycle specific for S-phase (dilapidated stairs) o Indications ▪ Hematologic malignancy (cracked cancer crab, antibody archers, and T-cell knights in rose window) ▪ Chronic inflammatory conditions, d/t immunosuppressive effects (torn antibody lantern). Include treatment of graft rejection, SLE, autoimmune hemolytic anemia, inflammatory myopathies, IBD (inflamed colonic haustra lanterns) ▪ Disease modifying anti-rheumatic drug (DMARDs) (joint lantern with inflammatory candle). Not as effective as MTX; usually used in refractory disease. o Adverse effects ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane on statue) ▪ Pancreatitis (pancreas sponge) ▪ Hepatotoxicity (both direct and d/t reactivation of latent infectious hepatitis) (liver spots) ▪ Inhibition of XO → increased 6-MP levels. Risk of adverse effects hugely increased with allopurinol or febustate coadministration (allopurinol nuns with purine beads) • Mycophenolate mofetil (Quasi-mofetil) o IMP dehydrogenase inhibitor, blocking GMP synthesis (knocking over grump statue) o Powerful anti-lymphoproliferative drug. Used in a variety of inflammatory and lymphoproliferative disorders (torn antibody lantern) o Adverse effects ▪ GI distress is common (queasy Quasimodo) ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane on statue) • All are phosphorylated to triphosphate form, which can incorporate into DNA → breaks or blockage of synthesis & repair by blocking DNApol-α & DNApol-β (cracked replication fork demonstrating gene flow out of Africa; cracked glass). Cell cycle specific for S-phase (Stone phase) • All share the same limiting toxicity: Myelosuppression & pancytopenia → immunosuppression (broken bone spilling marrow; immunocompromised cane) • Cladribine (clad in bearskins) o Cytotoxic purine analog (purine-shaped club) o Resistant to adenosine deaminase → ↑↑ intracellular levels. o Indications ▪ Hairy cell leukemia (hairy caveman) ▪ CLL, NHL • Cytarabine (saber-toothed tiger) o Cytotoxic pyrimidine analog (hexagonal patterned fur) o Only active against hematologic malignancies, e.g. AML, non-Hodgkin lymphoma (scratched out antibody archers, crab, & Tcell swordsman) • Gemcitabine (gems inside geode) o Cytotoxic pyrimidine analog (hexagonal patterned fur) o Active against both hematologic malignancies and solid tumors (tumorous rocks, with crab not scratched out) • Recall that an alkyl group is a molecular group with the formula -CnH2n+1. Alkylating agents add an alkyl group to nucleotide bases, most commonly to the guanine N7. This leads to the cross-linking of DNA strands, which causes DNA damage, interferes with DNA replication, and ultimately results in apoptosis. • Alkylating agents can act any point during the cell cycle. • Cyclophosphamide o The most commonly used alkylating agent (Cyclops Polyphemus). Like all of the alkylating agents, cross-links DNA (ankle chains). Once activated, forms a nitrogen mustard (similar to mustard gas). o Related agents are ifosfamide, melphalan, chlorambucil, mechlorethamine. o Activated by CYP450 in the liver (chariot with the CYP450 tag plate). o Indications ▪ variety of different cancers, both hematologic & solid tumors (sail torn through the image of a crab). ▪ Uniquely among the alkylating agents, used for autoimmune conditions (red lanterns look like immunoglobulins and are closer to the Cyclops than any of the other pharm avatars). o Toxicities ▪ Myelosuppression (bone club) ▪ An alternative metabolism pathway results in the toxic metabolite acrolein, responsible for several of the adverse effects of this drug ▪ Hemorrhagic cystitis caused by acrolein (red Greco-Roman fountain). Can preventatively administer mesna (“Maze”-na), the sulfhydryl group of which will bind acrolein and prevent the damage. ▪ ↑risk of bladder cancer (gold crab at the level of the bladder) ▪ SIADH & consequent hyponatremia (ADH bucket on cyclops head). Resultant encephalopathy in 10-30% of patients if not controlled. Worsened with hyperhydration during chemo, for unknown reasons. ▪ Infertility (M & F) & premature menopause (F) (dried up ovarian tree) ▪ Ifosfamide: Fanconi syndrome • Busulfan o Used for bone marrow ablation to prepare for BM transplant (beautiful sirens surrounded by cracked bones with bloody marrow exposed). Does not require bioactivation. o Toxicities ▪ Nigh universal severe myelosuppression (hence use as ablative) ▪ Lung toxicity, including acute ling injury, interstitial fibrosis, alveolar hemorrhage (sirens wearing golden chest plates with lung outlines) ▪ Hyperpigmentation – “busulfan tan” (dark-skinned sirens) • Nitrosoureas o include Carmustine, Lomustine, Streptozocin (mustang centaurs – sounds like -mustine; zebra striped centaur for streptozotocin). o Cross BBB, enabling treatment of CNS tumors including glioblastoma multiforme. o Toxicities ▪ CNS toxicities, including convulsions, dizziness, ataxia (centaur stumbling around clutching head) ▪ Myelosuppression ▪ Rarely, pulmonary fibrosis • Platinum-containing cancer chemo drugs include cisplatin, carboplatin, and oxaliplatin. All act by cross-linking DNA, similar to alkylating agents (double-helix chains with crossed links). Used to treat a variety of cancers, including solid tumors and hematologic malignancies (crumpled bag with a crab on it). • Toxicities: • Ototoxicity (gong-shaped earrings) results from targeting of outer hair cells in the Organ of Corti, causing a high frequency sensorineural hearing loss with tinnitus. Dose dependent. Cisplatin is notorious for this, although can also occur with high-dose carboplatin • Peripheral neuropathy in a stocking glove pattern (black arm gloves). Subacute neuropathy characterized by paresthesias and loss of sensation. Cisplatin > oxaliplatin >> carboplatin. • Nephrotoxicity & AKI, particularly with cisplatin (kidney shaped purse on Golightly’s flank). Can also cause acute tubular necrosis with muddy brown casts (muddy drainpipe). Two ways to prevent ATN o Amifostine, an organic thiophosphate, scavenges free radicals from cisplatin in the kidney (“Free Amethyst” sign over the visual of amethysts in a kidney-shaped purse) o Alternatively, IV saline diuresis (essentially induced polyuria) will flush toxic metabolites out of kidneys (cleaning the window with what appears to be a salt spray). • Myelosuppression, especially with cisplatin, and resulting immunosuppression (bone shaped box that has been depleted of its wares next to older woman with immunocompromised cane) • Certain antibiotics have anti-tumor activity so are used on cancer treatment (cancer crab). • Bleomycin o Uses iron & oxygen to induce free-radical formation → breaks in the DNA strands (bleomycin beluga is holding a rust-colored crab and breathing out bubbles which are breaking the double helix of kelp). Acts primarily during G2 phase (Galleon). o Used to treat testicular cancer & Hodgkin’s lymphoma. o Adverse effects ▪ Inactivated in the body by bleomycin hydroxylase. Tissues with lower production of this enzyme, notably lungs and skin, have more toxic effects. ▪ Pulmonary fibrosis, pneumonitis, pulmonary infiltrates (lung-shaped coral) ▪ Skin hyperpigmentation, classically in a striated pattern termed “flagellate erythema” (hyperpigmented stripes on beluga) ▪ GI adverse effects (sea urchin being eaten in the background) ▪ Myelosuppression, although less so than some other anti-cancer agents (bone shaped chest is sitting empty and has been cleaned out of treasure) ▪ Alopecia (whales are pretty bald) • Anthracyclines o Most commonly used doxorubicin & daunorubicin; less commonly, idarubicin, epirubicin, & mitoxantrone (Santa Anthracycline was apparently a pirate ship; chests of rubies remind of the -rubicin suffix). o Several mechanisms interfere with cancer growth: ▪ 1) generate free radicals in the presence of NADPH, oxygen, and iron (bubbles rising from the treasure chest). ▪ 2) Intercalate into DNA, causing breaks in the DNA, inhibiting with replication and transcription (rubies have become incorporated into the double-helices of the kelp near the chest). ▪ 3) Interfere with the action of topoisomerase II, preventing repair of DNA. Used in the treatment of both solid tumors and hematologic malignancies. o Toxicities: ▪ Cardiotoxicity, most often a dilated cardiomyopathy → SHF with ↓LVEF (this is rarely seen at low doses) (dilated heartshaped sacks sit next to the ruby chest). • Prevented with dexrazoxane, an iron chelating agent (skeleton on deck is holding a non-dilated heart sack, waving a rusted iron razor; “deck razor” sounds a bit like dexrazoxane) ▪ Myelosuppression (empty bone-shaped chest sits on the deck of the ship) ▪ Alopecia (skeletons don’t have hair) ▪ Mucositis and stomatitis • Actinomycin D/dactinomycin o Intercalates in DNA, blocking RNA synthesis (artifacts from the ship have intercalated into the kelp helices). o Often used to treat pediatric malignancies, including Wilms tumor, Ewing’s sarcoma, rhabdomyosarcoma (the child-sized doll is sitting off to one side). o Toxicities are the usual: myelosuppression & alopecia (creepy bald doll). • Topoisomerase enzymes relieve the tension in DNA supercoils by nicking and re-ligating the DNA. Topoisomerase I nicks ssDNA and is involved in the process of DNA unwinding during replication, while topoisomerase II breaks and re-ligates dsDNA breaks. The topoisomerase inhibitors interfere with one of these steps and are used in cancer treatment (crab flag). • Inhibitors all specific to S-phase of the cell cycle, preventing movement to G2 (Rapunzel cannot descend the Stairs because they are broken and the witch is Gone 2 the forest). • Etoposide & teniposide o inhibit topoisomerase II →↑DNA degradation. (Rapunzel is climbing down the side of the tower on two-strand twists; but both strands have broken!) o Used in treatment of solid tumors, particular testicular and small cell lung cancer, as well as leukemias & lymphomas. o Toxicities: ▪ Myelosuppression and consequent immunosuppression (empty bone-shaped luggage. Witch with immunocompromised cane) ▪ Alopecia (Rapunzel is losing a lot of hair) • Topotecan and irinotecan o topoisomerase I inhibitors (man’s toucan sounds like -tecan. Man has a single-stranded ponytail rather than a double-stranded twist). o Used to treat ovarian and small cell lung cancers; irinotecan is used in colon cancer. o Toxicities ▪ Myelosuppression ▪ Severe and profuse diarrhea, some days after initiating treatment, d/t cell toxicity in GI tract (bird pooping). Can be so severe as to cause volume depletion. • The taxols and the vinca alkaloids are all plant derived (yew and Vinca rosea, or periwinkle, respectively) and used in the treatment of cancer (forest setting; crab dinner). • Vinca alkaloids o bind β-tubulin, inhibiting polymerization into microtubules (woman – Cristine – is caught up in vines that look like metaphase spindles; the vines are breaking). This prevents mitotic spindle formation and results in M-phase arrest (monkey is swinging on vine, forming M shape). o Vincristine ▪ treats ALL, multiple myeloma, Hodgkin & non-Hodgkin lymphoma, and some pediatric tumors (Cristine). ▪ Toxicities: • Neurotoxicity, presenting with areflexia, peripheral neuritis and sensory neuropathy in a stocking glove pattern (Cristine is wearing stockings and gloves). Results d/t inhibition of axonal transport in the nerves. • Constipation and paralytic ileus (monkey with a plunger sitting on the outhouse) • Alopecia (bald monkey) o Vinblastine ▪ treat lymphomas and solid tumors (hunter blasting away with his gun). ▪ Toxicities • Myelosuppression (bones at the hunter’s feet). Note that this is not a side effect of vincristine. • Alopecia • Taxanes o hyper-stabilize β-tubulin in polymerized microtubules, arresting cells at the metaphase/anaphase transition (Tarzan is stabilized by a monkey holding his vine). o Used in breast and ovarian carcinomas, other solid tumors, small cell & non-small cell lung carcinomas. Are also a component of drug-eluting stents to prevent neointimal hyperplasia. o Toxicities: ▪ Hypersensitivity reactions are extremely common, in as many as 30% of patients. Can treat prophylactically with steroids, antihistamines. ▪ Alopecia ▪ Neurotoxicity, often presenting with burning paresthesias on extremities (Tarzan is holding Cristine’s glove) ▪ myelosuppression • Many cancers arise from kinase mutations → constitutive activation of proliferation signals, making these mutated kinases desirable targets for cancer therapy. • Many of the small molecule kinase inhibitors end in -nib (broken pen nib). Used to treat a variety of hematologic & solid malignancies (cracked crab bell). Tyrosine kinase inhibitors (inh (inhibited ibited tire sw swing) ing) • End in -tinib • Imatinib (imitating portrait of King George III) o Indications ▪ CML, characterized by increased levels of mature granulocytes, including eosinophils, neutrophils, basophils (colorful granules). Inhibits BCR-ABL fusion protein (“breakable” label) • BCR-ABL fusion protein results from t(9;22) – aka Philadelphia chromosome (hence the setting). The protein stimulates granulocytic precursors →CML. ▪ Blocks c-kit, found in GI stroma tumors (Congress Kit held by guy with beer belly & crab buttons) o Adverse effects ▪ Fluid retention → ankle & periorbital edema (king impersonator with baggy pantaloons) • Erlotinib (Earl of Tinib) o Blocks EGFR (Earl Geoffrey) ▪ Activation of EGFR → uncontrolled cell growth, metastasis, proliferation, angiogenesis. overexpressed in several solid tumors including non-small cell lung CA, pancreatic CA (crab on lung shaped lapel) o Adverse events ▪ Cutaneous involvement common, d/t EGFR expression in the skin. Classically papulopustular acneiform rash (Earl’s spotty rash) ▪ Diarrhea (muddy pants). Not usually severe. • Sunitinib (rising sun), Sorafenib (soaring eagle) o Inhibit multiple Y-kinases, including VEGF receptors – angiogenic growth factor . Result in blocking vasculogenesis needed for primary & metastatic tumors (hoeing up vegetables) o Indications: ▪ Sorafenib: RCC (flank crab suspender buckles), HCC ▪ Sunitinib: RCC (flank crab suspender buckles), GIST o Adverse effects ▪ Cutaneous effects including hyperkeratosis & rashes (farmer’s hyperkeratotic callouses & sunburn) ▪ ↑risk of hemorrhage, d/t disruption of VEGF-R on the vascular endothelium (farmer bleeding) • Vemurafenib (venomous snake) o -rafinib for B-Raf inhibit (B. FRA signature inhibited by broken nib). ▪ BRAF is a protein kinase involved in activation of melanocyte proliferation. V600E (valine → glutamic acid) seen in 4060% of patients with melanoma – hence vemu- for V→E mutated BRAF inhibitor. o Treats V600E BRAF positive malignant melanoma (disseminated ink). Improved survival & long-term events • Antibodies used in treatment of B-cell lines, created by a single cell line, hence monoclonal Ab. -mab = monoclonal Ab; -ximab = chimeric Ab – human derived + mouse derived variable region; -zumab = humanized Ab. • Rituximab (coronation ritual) o Chimeric Ab targeting CD20 (chimera sigil; XX straps). Results in in depleting B-cells and increases cellular killing via targeting for killing. o Indications ▪ CD20 ⊕ hon-Hodgkin lymphomas ▪ CLL (abnormal proliferation of abnormal B-cells & T-cells) (chronically worn tapestry with B-cell archers & T-cell knights) ▪ Disease modifying anti-rheumatic drug (DMARDs) (joint lantern with inflammatory candle). Usually in combination with MTX for treatment-resistant RA. ▪ Immunosuppressive therapy, including for granulomatosis with polyangiitis, microscopic polyangiitis (torn Ab lantern) o Adverse effects ▪ Immunosuppression (bishop’s cane). Not as much as one might expect, as Ig levels generally stay fairly normal. May see immunosuppression d/t neutropenia ▪ Hep B reactivation ▪ Rarely associated with progressive multifocal leukoencephalopathy, from the JC virus (laurel leaves) ▪ Infusion reaction common in 50% of patient. Presents headache, fever, rash, puritis, dyspnea, hypotension (swollen pink cherub with ivy). Thought to be d/t Ag-Ab interaction → activation of immune cells • Managed with antihistamines, acetaminophen, NSAIDS ▪ Serum sickness – type III HS reaction, resulting from tissue deposition of circulating immune complexes, causing fever, rash, arthralgia, proteinuria, LAD within 7-10 days (Delayed onset poisoning) • Occurs d/t targeting of non-human Ab components • Cetuximab (elephant tusks) o Binds EGFR (giraffe). EGFR acts via a tyrosine kinase. o Adverse effects ▪ Infusion reaction common in 50% of patients e.g. headache, fever, rash, puritis, dyspnea, hypotension (swollen pink cherub with ivy). Thought to be d/t Ag-Ab interaction → activation of immune cells • Managed with antihistamines, acetaminophen, NSAIDS ▪ Serum sickness – type III HS reaction, resulting from tissue deposition of circulating immune complexes, causing fever, rash, arthralgia, proteinuria, LAD within 7-10 days (Delayed onset poisoning) • Less common than in rituximab • Bevacizumab (beverage lady) o VEGF inhibitor by binding directly to VEGF (chopped vegetables). Anti-angiogenic (chopped vascular vegetables) o Useful for treating certain metastatic cancers (Cracked crabs) o Used for wet macular degeneration, characterized by retinal hypoxia → subretinal VEGF production → angiogenesis (pillow with macular wet spot) o Adverse effects ▪ Bleeding, sometimes serious and even fatal (bloody aprons) ▪ ↑thromboembolic events (clot cubes) ▪ GI perforation (perforated sack of vegetables). Most commonly in metastatic CRC, epithelial ovarian CA. • Alemtuzumab (Alms) o IgG monoclonal Ab that binds CD52 found on normal & malignant cells of lymphoid lineage (natural killer cells, B & T cells). Initiates direct cytotoxicity by recruitment of complement. (Alms-seeker is begging from archer and knight; 52 design etched on knight’s scabbard) o Used in treatment of CLL (chronically worn tapestry with B-cell archers & T-cell knights) o Adverse events ▪ Marrow suppression, increased risk of AI disorders, infection risk • Trastuzumab (tapestry weaver) o Monoclonal antibody against HER2/neu ⊕, a Y-kinase (tire swing with her 2 babies). Inhibits MAPK & PI3K/AKT signaling pathways, & facilitates antibody mediated destruction tumor cells. ▪ HER2 ⊕ seen in 20% of breast CA (crab bra), as well as adenocarcinomas of the ovary, lungs, stomach, salivary glands. o Adverse effects ▪ Cardiotoxicity (unraveling heart tapestry). Presents most often as ↓LVEF, less commonly as HF. Generally resolves with cessation of treatment.