Sketchy Pharmacology - Nucleoside, Nucleotide

• 6 classes of ARTs are combined depending on the characteristics of the patients, adverse effects, and bug profile. Usually 2 NRTIs + at least one other agent from a different class form the backbone of multidrug therapy. • Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs) (Knights of the Round Table). Act by competitive inhibition of HIV reverse transcriptase (reverse trasncriptum spell book has been stolen). Because NRTIs are nucleotides/sides, incorporate into DNA transcription but lack the 3’ hydroxyl, blocking 3’-5’ phosphodiester bond formation and causing premature chain termination (nucleoside mace with broken 3’ -OH group; page #s; broken helix bookmark) • “-dine” suffix attached to some of the NRTIS (meal) • Nucleosides must be phosphorylated & activated by cellular enzymes (activating Ⓟ scroll). • Shared adverse effects o All are associated with mitochondrial toxicity (table shape) o Lactic acidosis (sour milk) • Lamivudine (Sir Lancelot) o Used to treat Hep B (hippo, hippies, secret society banner). Especially helpful in HIV/Hep B coinfection. Note that in the latter case, discontinuation of the drug may lead to a hepatitis flair. o Adverse effects ▪ Peripheral neuropathy (Lancelot’s stockings and gloves) • Tenofovir (Sir Tristan) o Nucleotide not nucleoside (Tenofovir starts with a T) o As a nucleotide, does not need to be activated by cell enzymes (sailing on the tide while the others must wait inside, doesn’t need to wait for the Ⓟ signal) o Also has hep B activity • Zidovudine (Isolde with the dove crest) o Used during pregnancy and breastfeeding to reduce vertical transmission (pregnant woman) o Infants born to HIV+ mother usually receive several doses of zidovudine in the first weeks of life. o Adverse effects ▪ May cause myelosuppression (empty bone-shaped dish), causing anemia/neutropenia & agranulocytosis (white dress; sand timer) ▪ Lipodystrophy, with ↑central adiposity, ↓peripheral fat (silly looking horse) • Stavudine (Sir Steve) o Adverse effects ▪ Peripheral neuropathy (Lancelot’s stockings and gloves) ▪ Lipodystrophy • Didanosine (Sir Dan) o Major toxicity: dose dependent pancreatitis (pancreas shaped sponge) o ↑risk of peripheral neuropathy when coadministered with stavudine (Lancelot’s stockings and gloves) • Abacavir (abracadabra; merlin) o Hypersensitivity strongly associated with HLA-B 57:01 allele (Spell name). Presentation of cell peptides to immune system → delayed Type 4 HS reaction (he’s distracted and has a delayed reaction to spotted rash) • Emtricitabine (Excalibur) o Hyperpigmentation of palms and soles (badass gloves) • Non-nucleoside RT inhibitors. Do not need intracellular phosphorylated for activation. (Outside Camelot, so not knights of the round table; Ⓟ knight riding away toward Camelot) Bind directly to HIV RT resulting in allosteric inhibition, preventing viral synthesis of DNA polymerase activity (spell book blocked directly by arrow cleaving DNA bookmark) • Adverse effects o May have Life threatening hepatic failure within 6 weeks of starting therapy. Abrupt onset flu-like symptoms, abdominal pain, jaundice, fever (stag with yellow glow and liver shaped spot) o Teratogens (massive spider & pregnant lady) o Numerous drug-drug interactions d/t induction of CYP450 system (functional buggy with CYP450 plates). Both efavirenz & delavirdine activate & inhibit system, as well as broken down by it; nevirapine less activating. o Skin rash; Stevens-Johnson syndrome-TEN (orc with tengu mask) • Efavirenz (Elf Queen) o Principle adverse effects unique to efavirenz are all CNS. Include dizziness, drowsiness, headache, psychosis, insomnia, nightmares (queen clutching head; gazing at trippy antlers; dark night). • Delavirdine (Princess Delavir) o Not an NRTI despite the suffix! • Protease inhibitors often end in -navir suffix (Guinevere) including ritonavir, atazanavir, indinavir. Do not need Ⓟ by intracellular enzymes (knight running away with Ⓟ scroll). • HIV proteases serve to cleave the single long poly-protein product of the HIV gene products, which must be cleaved into proteins needed to construct virion particles (sword to cleave things). With proteases inactivated, the virion remains immature (immature page boy). • HIV pol gene encodes enzymes including RTs & proteases (Paul the blacksmith crafting protease blades). o Pol gene mutations → resistance. Never used as monotherapy, as may rapidly develop resistance to the entire class. • Adverse effects – many are metabolic o Hyperglycemia d/t insulin resistance, which may lead to diabetes eventually (elevated candy) o Dyslipidemias, with ↑TG & LDL (elevated butter) o Lipodystrophy (silly steed) o Inhibition of CYP450 (chrome bumper on inoperable wagon) causing numerous drug-drug interactions. Ritonavir especially (Right on! High fives) ▪ Can be used to advantage by boosting levels of other protease inhibitors ▪ Rifampin contraindicated when taking protease inhibitors d/t CYP450 activation → ↓protease inhibitor levels (rifampin crossbow utilized by wizardly henchman). May use rifabutin. • Indinavir (indigo princess) o May cause nephrolithiasis d/t urinary crystallization (stones in kidney fountain). May occur within days of beginning therapy. Adequate hydration is critical (drinking kid) • HIV infects macrophage, dendritic cells, & CD4 T-cells (crusader cross on neighboring castle). Once incorporated into host DNA, commandeers host machinery to transcribe viral genes. Gag, pol, env code for polyprotein precursors that produce viral virions, which will then bud off and invade next cells o gag structural gene encodes for virion core proteins, including p7 & p24 (sundial, gagged prisoners guarded 24/7) o env structural gene encodes envelope proteins including gp41 & gp120 needed for infiltrating membrane of host cells (envoy boat). Proteins are initially sent to the host cell ER for processing (reef around env boat) o pol gene encodes for proteases, reverse transcriptase, and integrase (Paul the blacksmith) • HIV invasion 1) For HIV to infect a cell, HIV surface glycoprotein gp120 must bind host cell CD4 molecule + a chemokine R (CCR5 or CXCR4) (envoy gaining entry with 120 battering ram; helper squire and CCR5 banners). 2) Fusion. Gp41 facilitates HIV fusion (envoy throwing 41 grappling hooks over castle walls). 3) Once inside the cell, RT transcribes viral RNA into dsDNA (reverso transcriptum spell book) 4) Integrase allows viral DNA to integrate into host cell DNA (keys to unlock nucleus of castle with double helix stairs) • Entry inhibitors o Maraviroc (rearing mare) binds CCR5 receptor, blocking HIV binding and consequent invasion. Before beginning therapy, should determine if HIV strain invades via CCR5. • Fusion inhibitors o Enfuvirtide binds gp41 surface protein, preventing fusion (knight on wall deflecting grappling hook; enfuvirtide for fusion) • NRTIs & NNRTIs act against RT (King Arthur & Queen Elfavir defending the castle) o Mutations to pol gene confer resistance to these classes as well as protease inhibitors & integrase inhibitors (Paul the blacksmith making swords, spell books, and keys for proteases, RT, & integrases respectively). • Integrase inhibitors o Raltegravir disrupts ability of HIV DNA to integrate into host chromosomes; may also be considered to prevent transcription of viral mRNA (knight deflecting key) o Mutations to pol gene confer resistance (mutated key not deflected by slacking knight) o May rarely cause rhabdomyolysis (bite out of chicken leg) • Interferons are host cytokines than produce antiviral, immunomodulating, & antiproliferative effects. Released by infected cells → intracellular signals activating immune response (virus infected manager is spreading cyto-coins). Upregulation of INF synthesis in infected cells accomplished by interleukins (Luke enabling activating kiddos). • Clinical uses of IFN-α (pachyderm man) o Interferon α treats hep B & C infections (hippo). Given as injections. Pegylated INF allows longer half-life and steadier concentrations, requiring less frequent dosing. o Approved for treatment of many neoplasms ▪ Hairy cell leukemia (hairy creatures) ▪ Malignant melanoma (melatonin ghost) ▪ Kaposi’s sarcoma by HHV-8 (Kate’s posies on cabinet and in maze) ▪ Renal cell carcinoma (crab in kidney shaped claw machine) o Condyloma acuminatum caused by HPV (pill bug jar) o Has many adverse effects (why we want new Hep C treatments!) ▪ Flu like syndrome with headaches, fevers, malaise, myalgias within 6h after dosing (fevered kid). In as much as 30% of patients after initiating therapy. Generally resolves. ▪ Neuropsychiatric complications with chronic treatment, including tinnitus, retinopathy, confusion, psych disturbances, profound fatigue (sick kid) • Depression resulting from INFα treatment can be profound and may include suicidal ideation. Contraindicated in severely depressed or suicidal patients. ▪ Pneumonitis, interstitial fibrosis ▪ Myelosuppression (maze is bone-shaped and red cell dots are being eaten). Important to consider when giving other myelosuppressive agents. ▪ Metabolic complications, including thyroid dysfunction, low-grade fever ▪ Dermatologic complications, e.g. alopecia ▪ Rarely, drug induced lupus (plush wolf in claw machine) • Interferon β (β Invaders) o Approved for use in relapsing type MS (“Combat lesions though Time & Space”) • Interferon γ (Gammaga game) o Treats CGD. May activate macrophage otherwise unable to form oxygen species needed for oxidative burst (bursting asteroids) • Hep C can cause acute and chronic hepatitis. Acute infection is often self-limited and commonly causes chronic infection. Decision of treatment regimen, dosing, and duration of therapy depends on stage & state of infection as well as infecting genotype (sketch of yellow hippo with genotype? highlighted). Fibrosis stage usually assessed as well, usually by history and exam; biopsy is not necessarily standard of care (stony “fibrosed” liver under microscope). • Treatment causes ↓M&M and improved quality of life in all patients with virologic evidence of chronic HCV infection (photographic evidence on board). Standard of care is to treat all HCV⊕ ⊕ patients except those with limited life expectancy. Goal of treatment is the eradication of viral RNA which is predicted by a sustained virologic response (i.e. HCV RNA not detected by PCR for 6 months after stopping treatment) (6 mos. sustained search for Sea Hippo). Achieving SVR means 99% change of sustained seronegativity on long term follow-up. • Treatment: Once weekly pegylated-IFN-α (α-antenna) + daily oral ribavirin (ribs) is traditional therapy. Several newer therapies with fewer adverse effects are available. • Ribavirin o Given oral daily as part of combination therapy along with pegylated-IFN-α o Guanosine nucleoside analog (purine shaped stakes). Needs Ⓟ by intracellular enzymes into active nucleotide form (3 pepper shakers) o Inhibits RNA production (RNA ropes) o Also used in RSV (though has largely been replaced with palivizumab) (RSV tombstone) o Adverse effects ▪ Dose dependent hemolytic anemia (tomatoes) ▪ Teratogenic – category X (enormous tarantula). Not to be used in M or F of childbearing age not on birth control. • Polymerase inhibitors: sofosbuvir (sofa with nucleoside pattern) o Nucleoside analog that inhibits the NS5B RNA-dependent RNApol inpatients infected by genotypes 1,2,3,4 (nucleotide pattern on sofa). o Direct polymerase inhibitor that disrupts RNA production (disrupted ssRNA rope) o May be part of a regimen with ribavirin, IFN-α, or the newer ones that are all oral; latter regimens highly effective & welltolerated, without interferon toxicities. o Adverse effects (tired Dr Livingstone) ▪ Fatigue ▪ Nausea • Protease inhibitors (NS3/4A inhibitors) (machete) o Simeprevir (and other protease inhibitors) work with HCV genotype 1 (simmering food over the fire). o Cleave HCV-encoded polyproteins o Adverse effects ▪ Photosensitivity & rash (flashing camera) ▪ Substrate & inhibitor of CYP450 system (broken down truck in the background) • New investigational drugs (North Sea investigative map) nd o 2 gen NS3/NS4A protease inhibitors o NS5A inhibitors o None require ribavirin & INF administration • Oral purine nucleoside analogs used for HSV (Hermes for herpes) & VZV (Zeus) infections • Acyclovir, valacyclovir, famciclovir all treat HSV. Short course of 7-10 d Tx with primary oral, genital, HSV infection → ↓viral shedding, time for lesion healing, and ↓local pain. Does not affect recurrence rates. o Can offer in recurrence daily to take any of the medications daily. Valacyclovir preferred as it is dosed qid & has superior bioavailability (“valet parking for frequent flyers” & “Daily rate” signs; attendant popping pills over “↑available↑” sign) o Can also be used as HSV prophylaxis in immunocompromised patients (lady with cane) ▪ In pregnancy with active recurrent genital herpes, give suppressant acyclovir at 36w to reduce risk of C-section & active shedding (pregnant lady) ▪ Transplant patients (organs on ice) • Acyclovir (recycling bins) o G-purine nucleoside analog that gets Ⓟ via herpesvirus encoded thymidine kinas → acyclovir monophosphate; occurs selectively in virus-infected cells (guanosine nucleoside shaped Gucci luggage labeled with Ⓟ luggage tag by Hermes attendant). This is the rate-determining activation step (“Rate limit”) (also the point where bugs can develop resistance). Subsequent Ⓟ steps taken over by cellular kinases (blue-collar workers slapping on 2nd & 3rd). Triphosphate can compete with deoxy-guanosine triphosphate. When incorporated, halts viral DNA synthesis via DNA-dependent DNA polymerase (bags jamming DNA-shaped conveyor belt) o Absence of thymidine kinase confers resistance (absence of attendant at closed baggage check) o Effective against herpes zoster (shingles is reactivated VZV) o Only drug here that is available for IV use in US (ivy). ▪ Treatment of serious HSV & VZV infection, including HSV encephalitis (helmet wings), neonate HSV infection (baby). • Valacyclovir o Acyclovir prodrug with better oral bioavailability (oral eating; ↑available) o Effective against herpes zoster (Zeus sign). Superior activity and less frequent dosing. ▪ Hasten resolution of cutaneous lesions & acute neuritis. ▪ Unknown effect on post-herpetic neuralgia. ▪ Valacyclovir & famciclovir are most effective when administered within 3d of symptom onset (“Great Value: 3-Day family vacation”) • Famciclovir o Effective against herpes zoster (“3-Day family vacation”) • Cidofovir (Cid the security guard) o Does not require viral kinase Ⓟ so effective against acyclovir or ganciclovir resistant HSV, VZV, CMV (Cid the security officer has Ⓟ tags so can bypass the closed luggage counter). This is especially important in immunocompromised patients, as thymidine resistant strains of VZV are found almost exclusively in immunocompromised populations o Directly inhibits viral DNApol (security officer directly turning off conveyor belts). • Foscarnet (car with a net) o Does not require Ⓟ by viral kinase (cart bypassing closed checkpoint). Active against acyclovir or ganciclovir resistant HSV, VZV, CMV. o Directly inhibits viral DNApol; pyrophosphate analog that selectively inhibits the pyrophosphate binding site on viral DNApols (security officer directly turning off conveyor belts). • Adverse effects o IV acyclovir can cause interstitial nephritis or crystalline nephropathy (sharp crystalline objects causing tubular obstruction in kidney shaped can). Uncommon with slower infusion rate & sufficient hydration (tossing water bottles) o All can cause CNS effects (delirium confusion, vertigo, hallucinations). Especially with high dose a/o IV administration (shaky kid setting off alarm in detector) • CMV infection (Mega-lo Market) occurs predominantly in immunocompromised, notably HIV (CD4 < 50) (“50 items or less” – should be “fewer”) & organ transplant (organ counter). Classically presents with CMV retinitis with retinal hemorrhages and infiltrates (pizza box). • Shared adverse effects o Associated with bone marrow suppression (bone marrow tray). Usually managed with hematopoietic growth factor s. Should be monitored for hematologic suppression. Effects may be additive with other myelosuppressive agents, especially with Zidovudine (pregnant princess eating bone marrow). • Ganciclovir (cans only recycle bins) o Guanosine analog, like acyclovir. Has to be tri-phosphorylated, before incorporating into viral DNA & jamming DNApol (jammed DNA conveyor belt). ▪ First Ⓟ step converts to ganciclovir monophosphate with a virus encoded kinase (UL97) which enables CMV-infected cell specificity (Market employee labeling Ⓟ for virus encoded . ▪ Following steps done by cellular kinases (kids going crazy with label guns) ▪ Protein kinase mutations can cause resistance o Incorporation stops DNA synthesis • Valganciclovir (great value samples) o Prodrug of ganciclovir with increased oral bioavailability (lady with open mouth) o As effective as IV ganciclovir for CMV retinitis o Used for prophylaxis in bone marrow & organ transplant (organs on ice) o Same MOA as ganciclovir • Foscarnet (fast car with a net) o Does not require Ⓟ by viral kinase. Active against acyclovir or ganciclovir resistant HSV, VZV, CMV. o Directly inhibits viral DNApol (kid crashing into register); pyrophosphate analog that directly selectively inhibits the pyrophosphate binding site on viral DNApols (bypassing phosphorylating CMV worker) o Available IV o Adverse effects ▪ May induce renal insufficiency. Appears to be directly toxic to renal tubular cells (spilled kidney beans) ▪ Hypocalcemia (broken milk bottles) ▪ Hypomagnesemia (falling magnets) ▪ Hypokalemia (banana peels) ▪ Seizures may result from electrolyte disturbances (shaky lines) • Cidofovir (Cid the security guard) o Does not require viral kinase Ⓟ so effective against acyclovir or ganciclovir resistant HSV, VZV, CMV (Cid the security officer has Ⓟ tags). This is especially important in immunocompromised patients, as thymidine resistant strains of VZV are found almost exclusively in immunocompromised populations o Directly inhibits viral DNApol (directly stopping DNA belt shut off switch) o Adverse effects ▪ Nephrotoxic, → proteinuria, azotemia, metabolic acidosis (broken kidney-shaped bottles) ▪ Must be coadministered with probenecid (probation officer Cid); blocks tubular secretion of cidofovir, limiting renal toxicity (probation offer protecting). Also blocks excretion and increases plasma concentration of many different drugs, including penicillins, MTX, & NSAIDS (druggie cashier not touching kidney bottles). CA can be treated with targeted radiotherapy, excision (local therapy) or systemic administration of cytotoxic drugs to eradicate or control proliferative cells, but affect systemic as well. CA cells produces larger amounts of DNA/RNA per unit time than most healthy cells, so affecting these pathways is highly attractive. • These agents affect thymidine synthesis, particularly those affecting folate cycle. • Thymidine is a pyrimidine deoxynucleotide (hexagonal plates), synthesized by thymidylate synthetase V @8G;L ?4G8F 7/ ' * ^ dTMP (dUMP dumplings → single dumpling with T-shaped chopsticks). Process powered by folate cycle: o Methylated THF (4 leaves + C-shaped sushi) converted to DHF (removing C-shaped sushi & knocking off 2 leaves). Catalyzed thymidylate synthetase. o DHF converted back to THF by DHFR (adding back 2 leaves). THF is then methylated (adding back C-shaped sushi). • Thymidine is only found in DNA. Ribonucleotides are synthesized first. So precursor to both thymidine & uracil is UDP (U Dining in? Please sign in!). , <5BAH6?8BG<78E87H6G4F8 6BAI8EGF/ ˚ * ^ 78BKL-UDP, which is precursor molecule (wait list waitress crossing out oxy). Antimetabol Antimetabolites ites • Methotrexate (MTX) (meat stix) o Folate analog competitively & irreversibly binds to DHFR, preventing THF renewal (meat stick chef has blocked leaf boats) ^ Buildup of folate & DHF (boat jam). Results in blocking de novo synthesis of DNA, RNA, and key cellular proteins. o Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) o Indications ▪ Treats a range of malignancies including leukemias, lymphomas, breast cancer, head & neck cancer, lung CA (cracked cancer crab) ▪ Treats non-neoplastic conditions with abnormal cellular proliferation • MTX + misoprostol as abortifacient (uterus-shaped backpack). Used for non-surgical treatment of early, unruptured ectopic pregnancy (baby keychain outside of uterus). Gestational trophoblastic neoplasia (choriocarcinoma, trophoblastic tumors, invasive molar pregnancy) V most can be treated with short course of MTX (mole for molar pregnancy) • Chronic inflammatory conditions, d/t immunosuppressive effects (torn antibody lantern) o Disease modifying anti-rheumatic drug (DMARDs). Effects take a few weeks (joint lantern with inflammatory candle). May manage with glucocorticoids, NSAIDs for short term SSx relief o Psoriasis (hyperproliferation of epidermis), as well as arthritis & nail disease (potentially d/t immunosuppressive effects) (silvery scaled kneepads) o Other inflammatory conditions, including IBD, SLE, Vasculitides, dermatomyositis o Adverse effects ▪ Folate deficiency (falling foliage) ▪ Megaloblastic (macrocytic) anemia d/t folate deficiency (blasting lanterns) ▪ Myelosuppression is the dose-limiting effect in high dosing needed for chemo. Causes immunosuppression (empty bone serving tray; immunocompromised cane) ▪ Pulmonary fibrosis (restrictive pattern) (restricted growth of lung-shaped bonsai tree) ▪ Hepatotoxicity, likely d/t direct cell damage (liver stain on apron). Monitor LFTs. ▪ Alopecia (bald chef) ▪ Stomatitis (burning mouth with hot meat) o Leucovorin rescue (folinic acid) can be used to reverse or prevent the worst of the adverse effects (maneki-neko, i.e.. lucky feline). Does not require DHFR for activation; displaced MTX from binding sites, restoring normal folate levels. • 5-fluorouracil (5-FU) (full guy waving 5 fingers) o Pyrimidine analog (hexagonal plates). Inhibits thymidylate synthase (guy blocking transfer of C-shaped sushi). Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) o Metabolized to active form, 5-dUMP. Forms complex with thymidylate synthase & DHF. Results in buildup of dUMP (dumpling buildup) o Indications ▪ CRC, breast, head & neck, liver, pancreas CA (cracked cancer crab) ▪ Topically for basal cell carcinoma o Adverse effects ▪ Diarrhea d/t damage of intestinal epithelium (patron with messy pants) ▪ Cutaneous complications • Photosensitivity (camera flash) • Hyperpigmentation • Number of other rashes ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane) ▪ No leucovorin rescue here! (falling feline) • Hydroxyurea (hydro-rock area) o Inhibits Ribonucleotide reductase (inhibited wait list waitress). Cell-cycle specific for S-phase (Sushi Phase, ramen DNA blocked by chopsticks) o Indications ▪ AML, CML, head & neck CA ▪ Sickle cell anemia, d/t ↑production of HbF (sickle by Zen garden; raising baby with Hb coin up) o Adverse effects ▪ Myelosuppression & pancytopenia → immunosuppression (empty bone serving tray; immunocompromised cane) ▪ GI upset