Exam 3 Flashcards

Question

What is Argatroban?

Answer 1

* Directly blocks active site on thrombin * Active on free and fibrin bound thrombin * Action is independent of AT-III * IV administration * Used in patients with risk of heparin-induced thrombocytopenia (HIT) * Used for treatment and prophylaxis in thrombosis patients * Monitor with aPTT

Answer 2

* Anticoagulant - direct thrombin inhibitor * Active on free and fibrin bound thrombin * Action is independent of AT-III * Oral administration * Used for prophylaxis DVT and thromboembolism (atrial fib) * Primarily excreted in the urine

Answer 3

* DEM (prodrug) is converted to Dabigatran (active) by plasma esterases * Converted to 4 different glucuronide metabolites (active) * Not a P450 substrate (so it has less drug interactions) * Substrate for P-glycoprotein transport

Answer 4

* Antidote: Idarucizumab * Humanized monoclonal antibody that binds to dabigatrin * 350x higher affinity for dabigatran than thrombin

Answer 5

* **Drugs**: Rivaroxaban, Apixaban * **MOA**: Binds directly to Factor Xa and prevents Xa from cleaving prothrombin to thrombin * Both drugs are substrates for CYP 3A4 and P-glycoprotein * **Administration**: Oral **Uses:** * Treatment for DVT and embolism * Prevent DVT following hip or knee replacement surgery * Reduce risk of srtoke in nonvalvular atrial fibrillation **Side Effects:** * Black box warning- bleeding can be life threatening * Bruising **Antidote for overdose** * Andexant recombinant factor Xa

Answer 6

* Aterial Thrombotic Disease, such as: * Transient ischemic attacks * Unstable angina * History of Myocardial infarction

Answer 7

* Antiplatelet drug * MOA: Inhibits platelet prostaglandin formation * Irreversible inhibitor of COX-1& COX-2 (acetylates the enzyme) * Reduces risk of second heart attack * Platelet prostaglandin formation (TXA₂ is inhibited by 80-160 mg/day Adverse effects: * Bleeding * GI irritation and ulcers

Answer 8

* Antiplatelet drug - inhibits platelet aggregation * **MOA**: Inhibits phosphodiesterase, which increases platelet cAMP levels * **Therapeutic use**: * Used with other agents, has very little benefit if given alone * Given with Warfarin for prevention of thromboembolism in pts with prosthetic heart valves

Answer 9

* **Drugs**: Clopidogrel, Ticagrelor, Cangrelor **MOA:** * Binds to P2Y₁ or P2Y₁₂ receptors to inhibit ADP binding * If ADP binds: * P2Y₁ activation causes TXA2 release, which increases PI hydrolysis and intracellular Ca. * P2Y₁₂ activation inhibits cAMP formation

Answer 10

* Antiplatelet drug **MOA:** * Clopidogrel - prodrug * Metabolized to active thiol metabolite, mediated by CYP 2C19 * Binds irreversibly to ADP P₂Y₁₂ receptor on platelets * Platelets need both P2Y₁ and P2Y₁₂ receptors for platelet activation * Inhibits ADP activation of IIb / IIIa complex needed for platelet aggregation * Must generate new platelets to reverse effects * Takes 7-14 days for platelet function to return to normal **Uses** * Prophylaxis for thrombosis **Side effects** * Bleeding * Monitor WBC and platelets * Thrombocytopenia purpura risk

Answer 11

* Antiplatelet drug * Reversible P2Y₁₂ platelet receptor inhibitor * Administered via IV * Half-life: 6 minutes * Effects reversed in 1 hour * Quickly dephosphorylated to the inactive metabolite * Used as treatment until oral agent is administered/starts working or during surgery

Answer 12

* **Abciximab** * Monoclonal antibody Fab fragment * Binds to IIb / IIIa receptor * More effective than Eptifibatide * Action lasts longer than the other two (>24 hours) * **Eptifibatide** * Peptide derivative * Action lasts 4-6 hours * **Tirofiban** * Non peptide * Action lasts 8 hours

Answer 13

**MOA** * Competitive reversible inhibitors * Inhibits interactions between Von Willebrand factor and fibrinogen with glycoprotein IIb / IIIa receptor * Binds to receptor to prevent platelet aggregation and crosslinking with fibrinogen **Uses:** * Acute coronary syndrome (unstable angina) * Prevents acute Adjunct with Angioplasty **Administration**: IV **Contraindications**: * History of hemorrhagic stroke * Active internal bleeding or GI/genitourinary bleeding in past 6 weeks * Thrombocytopenia * Major surgery or trauma in past 6 weeks * Do not use with Warfarin

Answer 14

* Fibrinolytic system is responsible for restricting clot progression beyond a site of injury * Also responsible for degrading fibrin during wound healing **How does it work?** * Plasmin - nonspecific protease that degrades fibrin, fibrinogen and other clotting factors * Plasminogen (in plasma) is the precursor to plasmin * Converted by t-PA, which is released by endothelial cells * t-PA binds to fibrin via lysine binding sites and activates bound plasminogen >300x more rapidly than it activates plasminogen in the circulation * Plasmin action on fibrinogen yields fibrinogen degradation products (FDP) which inhibit further conversion of fibrinogen --> fibrin **Natural regulation of fibrinolysis** * t-PA is inactivated by circulating plasminogen activator inhibitor-1 (PAI-1) * A2-antiplasmin binds covalently to plasmin at a lysine rich binding site causing inactivation (occurs only with circulating plasmin) * Lytic state: circulating plasmin > capacity of A2-antiplasmin * Ideal thrombolytic drug would degrade only desired thrombi and not old fibrin deposits

Answer 15

* Protein derived from beta-hemolytic streptococci **MOA:** * Combines with 1 molecule of Plasminogen to form a complex * The complex then converts a second molecule of Plasminogen to plasmin * Acts of fibrin bound and circulating plasminogen

Answer 16

**Use** * Reperfusion of occluded coronaries following an MI (works best if used within 4-6 hours of chest pain) * Pulmonary embolism * DVT * Arterial thrombosis **Adverse Effects** * 33% of people develop fever * Bleeding * Highly antigenic * Lytic state - * Excessive bleeding * Circulating plasmin exceeds capacity of A2-antiplasmin **Contraindications** * Surgery or trauma in past 10 days * Pre-existing bleeding disorder * Diastolic pressure > 110 mmHG * Intracranial trauma

Answer 17

* Streptokinase complexed with human lys-plasminogen * Active catalytic center is blocked by an acyl group. * Acyl group removed by plasma enzymes * Designed to provide more specific binding to thrombi * Less lytic state * Similar uses and side effects to streptokinase

Answer 18

**MOA**: * t-PA has high affinity for fibrin * Rapidly binds fibrin and activates fibrin-bound plasminogen * Low activity for circulating plasminogen * More specific than other agents for lysis of fibrin clot * Lower incidence of lytic state **Uses** * Reperfusion of coronary arteries in acute MI * Pulmonary embolism * Thrombotic stroke (use within 3 hours)

Answer 19

* Genetically engineered derivative of alteplase * Compared to alteplase, teneceteplase has: * More specific binding to fibrin * More specific resistance to PAI-1 * Longer half life * Higher incidence of reperfusion and functional outcome for ischemic stroke treated at 4.5 hours

Answer 20

* Bleeding * Inducing a hypocoagulable state * Patients bruise very easily * Any bleeding is difficult to stop

Answer 21

* Inhibitor of Plasminogen activation and fibrinolysis * Lysine analog competes for lysine binding sites on plasminogen and plasmin * Inhibits interaction of plasmin and fibrin

Answer 22

HIV: * Virus that causes HIV infection * Damages immune system by killing CD4 cells AIDS: * Last stage of HIV infection * As HIV infection advances to AIDS, the amount of HIV in your body increases and the amount of CD4 cells decrease * Without medicine, HIV progresses to AIDS in 10-12 years

Answer 23

* PrEP: pre-exposure prophylaxis (for HIV) * Taken every day before possible exposure * Can reduce risk of getting HIV from sex by >90%, and from injection drug use by >70% * PEP: post-exposure prophylaxis (for HIV) * Taken within 72 hours of exposure * Can prevent HIV infection when taken correctly, but not always effective

Answer 24

* First HIV injectable drug regiment * Combination of Cabotrgravir and Rilpivirine * Injected 1x/month * Before beginning Cabenuva: should take cabotegravir and rilpivirine as tablets (oral form) * Ensures the medications are well-tolerated before switching to injectable, extended-release formulation **Side Effects** * Injection site reactions, fever, fatigue, headache, MSK pain, nausea, sleep disorders, dizziness, rash * Should not be used in pts with previous reaction to cabotegravir or rilpivirine, or in pts who are not virally supressed (HIV-1 RNA > 50 copies/mL)S

Answer 25

1. Binding * HIV attaches itself to the CD4 receptor of the T4 cell 2. Fusion * HIV cell fuses to the outside of the cell 3. Reverse transcription * HIV carries 2 strands of RNA, which are released after the binding process * Reverse transcriptase (viral enzyme) allows RNA to make a DNA copy (called the proviral DNA) 4. Integration * HIV DNA is carried into the host's nucleus, where the viral enzyme integrase hides proviral DNA until the cells wants to make more proteins (thus, making more HIV) 5. Transcription * Viral DNA separate and special enzymes make complementary mRNA 6. Translation * mRNA is processed and corresponding strand of HIV proteins are made 7. Viral Assembly + Maturation * Long strands of viral proteins are cut up by protease into smaller proteins that serve as enzymes or elements of new HIV * Once new HIV is assembled, they bud off and create a new virus

Answer 26

* Reduce HIV related morbidity and prolong survival * Improve quality of life * Restore and preserve immunological function * Maximally and durably suppress HIV viral load * Prevent vertical HIV transmission

Answer 27

**CD4 T Cell Count** * Major clinical indicator of immunocompetence in HIV infections * Usually the single most important decision to initiate therapy * Strongest predictor of subsequent disease progression and survival * Repeated every 3-6 months to reassess **Viral Load Testing** * Obtain plasma viral load at initiation, repeated in 2-8 treatment after treatment initiation or alterations in therapy * Once antiviral regiment is stable, check every 3-4 months **Genotype Assays** * Detect drug resistance mutations in relevant viral genes * Turnaround is 1-2 weeks after collection **Phenotypic Assays** * Measure the ability of a virus to grow in different concentration of antiretroviral drugs * Expensive

Answer 28

* Candidiasis * Cytomegalovirus disease * Mycobacterium avium complex * Wasting syndrome caused by HIV * Pneumocystis carinii pneumonia * Cryptococcosis * Kaposi's sarcoma * Toxoplasmosis of the brain

Answer 29

**CD4 Count < 200** * Pneumocystis carinii pneumonia (PCP) * Px: Bactrim DS daily, or 3x/weekly **CD4 Count < 100** * Toxoplasmosis * Px: Bactrim DS daily **CD4 Count < 50** * MAI/MAC + CMV (Mycobacterium, Cytomegalovirus) * MAC Px: Azithromycin 1200mg/week * CMV Px: Ganciclovir

Answer 30

* Maintenance of higher CD4 count * Prevention of irreversible damage to the immune system * Decrease risk of HIV complications * TB * Kaposi's sarcoma * Peripheral neuropathy * Non-Hodgkin's lymphoma * HIV-associated cognitive impairment * Decrease risk of non-opportunisitic conditions * CAD * Renal disease * Liver disease * Non-AIDS related malignancies and infections

Answer 31

* Development of treatment related side effects or toxicities * Development of drug resistance * Results in loss of future treatment options * Decreased time for patient to learn about disease state of HIV * Acceptance of new diagnosis * Acceptance of lifestyle changes and notification to significant others * Decreased amount of time to prepare for acceptance of adherence to therapy * Treatment requirements and options

Answer 32

* CCR5 Antagonists (entry inhibitor) * Fusion inhibitors (entry inhibitor) * NNRTIs (non-nucleoside reverse transcriptase inhibitors) * NRTIs (nucleoside reverse transcriptase inhibitor) * Integrase inhibitors * PIs (Protease inhibitors)

Answer 33

* Booster of HIV treatment * Always used in a combo, no antiviral activity itself * Often used with Elvitegravir * Part of "Quad Pill" - Stribild * Potent inhibitor of CYP 3A * Pharmacokinetic enhancer of atazanavir or darunavir

Answer 34

**MOA** * Binds to the CCR5 receptor of the CD4 T-cell * Inhibits virus entry into cell **Key Points** * Restricted to HIV infected patients that are infected with CCR5 tropic virus **Adverse Effects** * Abdominal pain * Rash * Upper respiratory tract infections/cough * Dizziness/orthostatic hypotension * MSK symptoms

Answer 35

**MOA** * Interferes with entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes * Binds to the first HR1 in the gp41 subunit of the viral envelope glycoprotein * This prevents the conformational changes required for the fusion of viral and cellular membranes **Key Points** * Administrations: s.c. injection * Cost, inconvenient delivery system, cutaneous toxicity **Adverse effects** * Hallmark adverse reaction: Injection site irritation * Nodules, erythema * Hypersensitivity reaction (< 1%) * Rash, fever, N/V, chills/rigors, hypotension, elevated liver enzymes

Answer 36

**MOA** * NNRTIs: Non-nucleoside reverse transcriptase inhibitors * Bind directly to the reverse transcriptase * Do not need phosphorylation like the NRTIs * Not incorporated into the viral DNA **Key points** * Quick resistance may develop * Extensive resistance across the class * Mandatory to use w/ 2 other active agents * Long half life * May lead to one of these drugs exposed to HIV as monotherapy

Answer 37

* **Rash** * SJS, has highest incidence with Nevirapine * Frequently occur within first 2-4 weeks of therapy * **Neuropsychiatric symptoms** * Most common with Efavirenz * Often subsides after 2-4 weeks * Dizzy, drowsy, insomnia, abnormal dreams, confusion, abnormal thinking, impaired concentration, amnesia, agitation, hallucinations, euphoria * **Increased transaminases reported with most NNRTIs** * Nevirapine > other NNRTI * Nevirapine has greatest risk in AVR naive pts * 2 week dose tapering can decrease hepatic effects and rash risk

Answer 38

**MOA** * NRTIs: Nucleotide Reverse Transcriptase Inhibitors * Phosphorylated intra-cellularly, then incorporate themselves to block reverse transcriptase * Similar to the building blocks of RNA and DNA **Key points** * Variable metabolism and renal excretion * Some very high/low * Food effects on AUC * Didanosine: decreased 55% by acidity * Zidovudine: decreased by 24% with high fat food

Answer 39

* Didanosine - decreased 55% by acidity * Zidovudine - decreased by 24% with high fat meal

Answer 40

* NRTI, but a nucleoTide, instead of nucleoSide * Slightly different mechanism allowing continued efficacy against HIV strains resistant to other NRTIs * **Adverse effects**: * Lactic acidosis with hepatic steatosis (fatty liver) * Decreased bone density * Acute exacerbation of hepatitis, if co-infected with Hepatitis B * **TDF**: tenofovir disoproxil fumarate * Associated with proximal renaltubulopathy and decreased bone mineral density * **TAF**: tenofovir alafenamide * Preferred tenofovir product

Answer 41

**MOA** * Inhibits strand transfer of viral DNA to host cell DNA **Key points** * Used for HIV pts that have tried other treatment options already ("treatment experienced") **Adverse effects** * Nausea, diarrhea, headache * Fever * Elevated CPK (muscle weakness, rhabdo)

Answer 42

* MOA: Inhibit HIV-1 protease * HIV-1 protease is responsible for cleaving large viral polypeptides into smaller functional virons * All PIs are cleared via Hepatic oxidative metabolism * All are inhibitors of 3A4, to varying degrees * Effects of food on PIs are "all over the board" * Ritonavir "booster" allows for lower doses of PIs and takes away the "pill burden" for several antivirals

Answer 43

* Endocrine-type side effects * Hyperlipidemia * Fat metabolism * Insulin resistance/diabetes * Osteonecrosis * Increased risk of spontaneous bleeding * Increased risk of hepatitis (drug induced) * In some studies, PIs are associated with MIs and strokes

Answer 44

* HIV booster * Allows for lower dose of HIV antiviral or less "pill burden" * Associated with increased LDL, TG, HDL * Adverse effects: paresthesias, taste disturbances/anorexia

Answer 45

Cytosine arabinoside Hydroxyurea

Answer 46

6-mercaptopurine Methotrexate

Answer 47

Vincristine Vinblastine Paclitaxel

Answer 48

Alkylating drugs Nitrosoureas Antitumor antibiotics Procarbazine Cisplatin Decarbazine

Answer 49

Mecholrethamine Cyclophosphamide Ifosfamide Melphalan Chlorambucil

Answer 50

Carmustine Streptozocin Bendamustine

Answer 51

Procarbazine Dacarbazine Temozolomide

Answer 52

1. Activation * Nucleophilic attack of unstable aziridine ring by electron donor 2. Mispair substitution * Modified guanine can mispair with thymine residues during DNA synthesis, leading to substitution of thymine for cytosine 3. Excision * Alkylation creates lability in the imidazole ring, leading to opening of the ring and excision of the damaged guanine residue * Mispairing and imidazole ring opening can lead to attempts to repair the damaged stretch of DNA, causing strand breakage 4. Cross-linking two nucleic acid chains * Bifunctional alkylating agents (like nitrogen mustards) can undergo a similar cyclization reaction and alkylate a second guanine residue or another nucleophilic moiety, resulting in the cross-linking of two nucleic acid chains or linking the nucleic acid to a protein * Lethality of DNA alkylation depends on the recognition of the adduct, the creation of the DNA strand breaks by repair enzymes, and an intact apoptotic response

Answer 53

* Prodrug. Requires in vivo activation by CYP 2B * Byproduct is a toxic metabolite called acrolein. Causes hemorrhagic cystitis, which reacts with the bladder wall * Side effects caused by acrolein can be prevented with co-administration of 2-mercaptoethanesulfonate (conjugates acrolein in urine) * Can cause SIADH * Used for: Non-hodgkins, ovarian, breast cancer

Answer 54

* Analog of cyclophosphamide * Requires in vivo activation by CYP 3A4 * Common component of high-dose chemotherapy (HDC) with stem cell rescue * Toxicity similar to cyclophosphamide * Highly neurotoxic, can be prevented with methylene blue

Answer 55

* Primarily a myelosuppressive agent used for CML * Replaced by imatinib mesylate (GLEEVEC) * Common after high dose - VOD and pulmonary fibrosis * Used in combo with cyclophosphamide to prepare for bone marrow transplantation * Suppresses all blood elements, particularly stem cells * Produces prolonged and cumulative myelosuppression lasting months. (With myelosuppression comes immune suppression)

Answer 56

* Important component of CNS malignancies * Highly lipophilic * Highly carcinogenic and mutagenic

Answer 57

* High affinity for B-cells in the pancreas * Used for inducing insulin-dependent diabetes in experimental animals

Answer 58

* All - highly toxic to dividing mucosal cells and to hair follicles, leading to oral mucosal ulceration, intestinal denudation, and alopecia * Nitrogen mustards - nausea and vomiting

Answer 59

* Multiple myeloma * Nitrogen mustard alkylating agent

Answer 60

* Standard for chronic lymphocytic leukemia * Nitrogen mustard alkylating agent

Answer 61

* **Decreased permeation** of actively transported drugs (mechlorethamine, melphalan) * **Increased** intracellular concentrations of nucleophilic substances (mostly thiols such as **glutathione**), which can conjugate with/detoxify electrophilic intermediates * **Increased activity of DNA repair pathways** * **Increased rates of **metabolic degradation** of the activated forms of cyclophosphamide and ifosfamide * **Impaired apoptotic pathways**, with overexpression of **bcl-2** as an example

Answer 62

* Cisplatin, carboplatin, oxaliplatin * Part of the alkylating agents superfamily * Bind to nucleophilic sites on DNA and cause DNA damage, similar MOA to alkylating agents * Mutagenic, carcinogenic, teratogenic * Inside cell, chloride is replaces by water and the drug is activated. High concentrations of chloride stabilize the drug, reducing its cytotoxicity

Answer 63

* Very useful for solid tumors: testicular, ovarian, head/neck, lung cancers * Milder myelosuppression than alkylating agents * Can cause severe CNS toxicity - nausea, vomiting, peripheral neuropathy * Nephrotoxicity and ototoxicity - nephro can be reduced by chloride diuresis, oto cannot

Answer 64

* Designed to block DNA synthesis * Based on idea that cancer cells divide more rapidly than normal cells, so more vulnerable * Many antimetabolites produce cell death by triggering apoptosis (cytotoxic) * Most are nucleoside analogs that interfere with DNA synthesis or block methylation of uracil to thymidylate

Answer 65

Methotrexate Pemetrexed Trimetrexate

Answer 66

Fluorouracil Cytarabine Gemcitabine

Answer 67

Mercaptopurine Pentostatin

Answer 68

* Essential dietary factor, from which THF cofactors are formed, which provide single carbon groups for the synthesis of precursors of DNA and RNA * DHFR enzyme reduces folate to dihydrofolate and then to tetrahydrofolate

Answer 69

* Inhibits dihydrofolate reductase (DHFR) to block biosynthesis of thymidylic acid and purines (which decreases DNA synthesis) * Directly inhibits thymidylate synthase, GAR formyltransferase, AICAR formyltransferase * Affinity of MTX for DHFR is much higher than folate, so it can selectively bind to DHFR and inhibit it * S phase-specific self-limiting

Answer 70

* Citrovorum, folinic acid * Minimizes toxic effects of folate depletion (due to MXT and PEM) * Bypasses the metabolic block induced by MTX, but does not diminish anti-tumor activity * Potentiates 5-FU

Answer 71

* Critical drug for childhood ALL * Intrathecal administration in adults for meningeal leukemia or lymphoma * High dose MTX with leucovorin rescue (HDM-L) is used in osteosarcoma * Non-neoplastic uses: disabling psoriatic or rheumatoid arthritis

Answer 72

* Particularly useful for mesothelioma * Many similar uses as MTX

Answer 73

* Limited neurotoxicity (polar compound, cannot cross BBB) * Chronic administration for non-neoplastic indications can cause **hepatic fibrosis** * Reduce dose in ptns with **renal dysfunction** * Severe myelosuppression * Mucositis and GI toxicity * MTX Glu2-5 are retained in hepatic and renal tissues for long periods of time, causing prolonged suppression of DHF in these cells

Answer 74

* Increased cellular DHFR * Altered DHFR * Reduced conversion to polyglutamate form * Efflux of the drug from the cell

Answer 75

* Either inhibit nucleotide synthesis or get incorporated into the DNA (thus blocking its function) * Small structural modifications of the base and deoxyribonucleoside to create each drug

Answer 76

* Capecitabine is a prodrug with little pharmacologic activity until it is converted to 5-FU by thymidine phosphorylase * 5-FU activated by complex series of enzymatic reactions, to ribosyl and deoxyribosyl nucleotide metabolites * FdUMP (metabolite) forms a covalently bound ternary complex with enzyme TS and reduced folate 5,10-methylenetetrahydrofolate * This results in inhibition of DNA synthesis through "thymineless death" * FUTP (metabolite) is incorporated into RNA, where it interferes with RNA processing and mRNA translation * FdUTP (metabolite) can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function

Answer 77

* Used in colorectal and gastric cancer treatments * Combination with platinum compounds dramatically increases efficacy in colorectal cancers * May also be used in combo regimens for metastatic breast cancers

Answer 78

* 5-FU: myelosuppression, alopecia, dermatitis, nausea, vomiting * Capecitabine: similar profile as 5-FU, but also increased incidence of hand-and-foot syndrome (tingling/burning/numbness, redness/swelling, flaking/peeling skin, small blisters, sores/breaks in skin, discomfort, pain)

Answer 79

Either inhibit nucleotide synthesis or get incorporated into the DNA (thus, blocking its function)

Answer 80

* Most important antimetabolite used in therapy of AML. Single most effective agent for induction of remission in this disease * Potent myelosuppressive agent capable of producing acute, severe leukopenia, thrombocytopenia, and anemia with striking megaloblastic changes * Enters cells using hENT1 (nucleoside transporter) * Ara-C must be activated to Ara-CMP and eventually Ara-CTP * Ara-CTP competes with physiological substrate dCTP for incorporation into DNA by DNA polymerase * Incorporated Ara-CMP residue is a potent inhibitor of DNA polymerase, both in replication and repair synthesis, and blocks the further elongation of the nascent DNA molecule

Answer 81

* Important drug for ptns with metastatic pancreatic; non-squamous, non-small cell lung; and bladder cancer * Principle toxicity is myelosuppression. Longer duration infusions = greater myelosuppression and hepatic toxicity * Hemolytic uremic syndrome - can occur in rare cases

Answer 82

* Either inhibit nucleotide synthesis or get incorporated into the DNA (thus, blocking its function) * Uses HGPRT enzyme in purine salvage pathway to inhibit de novo purine biosynthesis

Answer 83

* Rarely used to treat cancer * Most commonly used as an immunosuppressant * Prodrug. Must be converted to active metabolite 6-mercaptopurine * MOA - drug metabolism results in the incorporation of thiopurine analogs into the DNA structure, causing termination and cytotoxicity

Answer 84

* Active drug form of Azathioprine * Used mostly for treatment of childhood acute myeloid leukemia (AML) * Significant toxicity: Myelosuppression * S phase-specific self-limiting

Answer 85

* Acute lymphoblastic leukemia (ALL) * Acute myelogenous leukemia (AML) * Myelosuppression

Answer 86

1. Infected mosquito injects sporozoites (when biting a human) 2. Sporozoites migrate to liver where they form merozoites. 3. Merozoites are released and invade red blood cells 4. Rupture of red blood cells release merozoites which can infect other red blood cells. 5. Female mosquito picks up gametocytes from infected individuals.

Answer 87

Chloroquine Quinine Mefloquine Pyrimethamine Chloroguanide

Answer 88

Primaquine

Answer 89

Primaquine

Answer 90

* Suppressive therapy: elimination of parasite form responsible for acute symptoms. Does not prevent infection b/c the sporozoites survive and invade the liver with the development of liver-stage parasites * Clinical: removal of all parasites from blood * Radical: elimination of all parasite forms from the body

Answer 91

* MOA * Targets blood stage of parasites * Inhibitor of the production of hemozoin * CYP 2D6 inhibitor * Uses * Asexual and erythrocytic forms of susceptible parasites * Moderate activity against gametocytes * Used as chemoprophylactic drug in regions which report chloroquine-sensitive disease * No longer primary cure for Malaria due to resistance * Not recommended for ptns with epilepsy or myasthenia gravis

Answer 92

* Headache, nausea, vomiting, blurred vision, dizziness, fatigue, confusion * Rare: depigmentation of hair, corneal opacities, hematological disorders, exacerbation of psoriasis, dose-related retinopathy, hemolysis of G6PD deficient ptns * CYP 2D6 inhibitor * Not recommended for treating ptns with epilepsy or myasthenia gravis * Contraindicated in psoriasis and retinal disease

Answer 93

* MOA * Not completely understood * Targets liver stage parasites, eliminates hypnozoites, gametocytocidal * May be acting by generating free radical reactive oxygen species, which kill the parasite * Uses * Only agent available for treating hepatic primary and hypnozoite forms of P. vivax and P. ovale in liver (radical cure) * Used after chloroquine treatment or shortly before/right after chloroquine prophylaxis ends * Toxicity * Low incidence of toxic side effects in most ptns * Mild abdominal distress, methemoglobinemia, hemolysis in G6PD deficient ptns

Answer 94

* MOA * Not completely understood, may be similar to chloroquine * Drug of choice for parenteral therapy in chloroquine-resistant P. falciparum * Being replaced by oral and parenteral artemisinins * Adverse Effects * EKG changes, hypotension

Answer 95

* MOA * Targets blood stage parasites * Targets 80S ribosome to inhibit protein synthesis in parasites * Forms complex with heme, which is toxic to parasites * Use * Useful chemoprophylactic agent for travelers spending weeks-years in areas where infections are endemic * Toxic effects * Vivid dreams, neuropsychiatric symptoms in 10% ptns * Short-term: nausea, vomiting, dizziness * May cause CNS toxicity in ptns with malaria - seizures, confusion, acute psychosis, disabling vertigo

Answer 96

* MOA * Binds to and reversibly inhibits DHFR in the parasite (folate synthesis enzyme) * Used against P. malariae and Toxoplasma gondii * Adverse Effects * Hypersensitivity and hematologic reactions * Anemia due to decrease in folic acid (leucovorin rescue to help)

Answer 97

* Used for malaria chemoprophylaxis and treatment of uncomplicated P. falciparum malaria in adults and children * Effective against asexual blood forms and liver stages of P. falciparum (not P. vivax). * Moderate activity against gametocytes * Atovaquone - mitochondrial toxicant in parasites * Proguanil - in cyclic active form, inhibits dihydrofolate-thymidylate synthase (which decreases DNA synthesis)

Answer 98

* MOA * Targets liver stage parasites, gametocyte-killing activity * Production of free radicals * Binds covalently to malaria proteins and damage the parasite * Produces toxic heme adducts and oxidant stress * Use * Generally not used alone, but in combo with other drugs for treatment of severe P. falciparum malaria * Not for chemoprophylaxis

Answer 99

* Chloroquine (or hydroxychloroquine) - restricted to areas with chloroquine-sensitive malaria * Mefloquine - areas with mefloquine-sensitive malaria * Atovaquone-proguanil (Malarone) - all areas * Primaquine - short stays in areas with P. vivax; anti-relapse therapy for P. vivax and P. ovale

Answer 100

* Symptoms * Diarrhea, foul-smelling greasy stools, abdominal cramps, flatulence, fever, malaise * Treatment * Metronidazole * Paromomycin * Tinidazole * Nitazoxanide

Answer 101

* Prevalence * Highest in people who are institutionalized, have AIDS, foreign travel, immigrants/migrant workers * Presentation * Abdominal cramping, bloody diarrhea * Right side pain * Hepatomegaly - suggests liver abscess

Answer 102

1. Ingestion of cysts 2. Formation of trophozoites 3. Penetration of intestinal wall 4. Multiplication of trophozoites 5. Systemic invasion 6. Cysts discarded with feces

Answer 103

Diloxanide furoate Paromomycin Tetracycline Iodoquinol

Answer 104

Metronidazole Tinidazole

Answer 105

* (Drugs that treat liver abscesses and intestinal wall infections) * Bowel wall only * Tetracycline * Erythromycin * Liver only * Chloroquine * Other * Emetine * Dehydroemetine

Answer 106

* MOA * Systemic and luminal activity (mixed) * Metabolites of metronidazole bind to DNA and protein of parasite, generating ROS * Adverse effects: * Abdominal cramping, constipation, metallic taste * Inhibits alcohol aldehyde dehydrogenase (no alcohol can be consumed with metronidazole)

Answer 107

* Luminally active - eradicates luminal trophozoite and cyst forms of E. histolytica * Adverse Effects * Abdominal cramps, diarrhea * Seizures, encephalopathy * Dose-dependent peripheral neuropathy

Answer 108

* Only effective against luminal forms of E. histolytica and tapeworm * Adverse effects - abdominal cramps, potentially nephro- and oto- toxic

Answer 109

* Intramacrophage protozoa of genus Leishmania * Transmitted to humans by female sandfly * Cutaneous, mucocutaneous, visceral forms * Drugs of choice: * Sodium Stibogluconate - all Leishmania * Miltefosine - Cutaneous, Mucocutaneous, Visceral * Liposomal Amp B - Visceral * Paromomycin - Cutaneous, Visceral

Answer 110

* Transmitted by blood-sucking triatomine bugs * Acute phase - usually no symptoms, but sometimes fever, rashes, diarrhea, spleen enlargement * Chronic phase - irregular heartbeat, enlarged esophagus, heart failure, cardiac arrest * Drugs of choice * Nifurtimox, Benznidazole * Both agents suppress parasitemia and cure the acute phase * Both must be taken for long periods

Answer 111

* Transmitted by Ts-tse fly * Stage 1: parasites detected in blood and lymph; no CNS involvement * Stage 2: CNS involvement, inflammation of brain and spinal cord, leading to lethargy and continuous sleep * Drugs of choice * Pentamidine, Suramin - Stage 1 * Melarsoprol - CNS involvement * Nifurtimox/eflornithine combo (NECT) - Stage 2

Answer 112

* Can contract by: * Ingestion of undercooked meat and contaminated vegetable-containing tissue cysts * Direct oral contact with feces of cats shedding oocysts * Transplacental fetal infection with tachyzoites from acutely infected mothers * Drugs of choice * Pyrimethamine + sulfadiazine * Alternative - Pyrimethamine + clindamycin * Spiramycin - for acute acquired toxoplasmosis in early pregnancy

Answer 113

* Drug of choice for Pinworm, roundworm, whipworm, hookworm * MOA * Selectively binds to helminthic tubulin and blocks microtubule assembly in helminths * Inhibits glucose uptake, resulting in immobilization and death * Adverse effects - sometimes abdominal pain, but relatively no side effects at normal doses

Answer 114

* Strongyloidiasis - Threadworm * Drug of choice - Ivermectin * MOA * GABA receptor agonist * GABA controls neurotransmission by sending inhibitory signals to motor neurons * Ivermectin potentiates these inhibitory signals, and causes paralysis in threadworms * Adverse effects * Minimal - GI complaints, drowsiness

Answer 115

* Praziquantel is used to treat all forms of schistosomiasis (flatworms) * MOA - increased trematode cell membrane permeability to calcium, causing paralysis of organism * Adverse effects - general ill feeling, headache, dizziness, nausea, stomach discomfort, fever, rash

Answer 116

* Enterobiasis - Pinworm Pyrantel pamoate Mebendazole Albendazole

Answer 117

* Ascariasis - Roundworm Pyrantel pamoate Mebendazole Albendazole

Answer 118

Diethylcarbamazine

Answer 119

* Trichuriasis - Whipworm Mebendazole Albendazole

Answer 120

Albendazole > Mebendazole, Pyrantel pamoate

Answer 121

* Strongyloidiasis - Threadworm Ivermectin Alternative - Thiabendazole

Answer 122

Idiopathic Renal clearance mechanisms Increased nucleic acid turnover Specific enzyme effects Local factors Possible tissue factors

Answer 123

* Avoid obesity and exercise regularly * Avoid eating food with high purine content * Avoid dehydration * Dehydration increases uric acid in serum and can promote urate crystal formation * Avoid alcohol * Decreased alcohol dehydrogenase can increase levels of uric acid in serum * Alcohol promotes lactate formation and decreases pH, which can accelerate urate crystal formation

Answer 124

* MOA * Causes cell cycle arrest * Depolymerization of microtubules of neutrophils * Alters neutrophil motility and chemotaxis * Inhibits inflammasome activation * Pharmacokinetics * Mediated by CYP 3A4 * Substrate for P-glycoprotein * Drug accumulates in liver, kidney, spleen * Do not co-administer with CYP 3A4 or P-glycoprotein inhibitors

Answer 125

* Two consecutive courses should be done at least 3 days apart * Ptns with hepatic or renal disease - reduce dose * Very effective in acute attack (flare) of gout * Prophylactic agent to prevent recurrent attacks of gout

Answer 126

* GI toxicity - nausea, vomiting, diarrhea, abdominal pain * Acute toxicity - multifocal gastric mucosal hemorrhage * Myelosuppression, leukopenia, granulocytopenia, thrombopenia, aplastic anemia, rhabdomyolysis * Rare - hair loss, corneal opacities, hematological disorders, rash/hives, hemolysis in G6PD deficient ptns * Should not be used with CYP 3A4 or P-glycoprotein inhibitors

Answer 127

* Uses * Chronic gout, secondary hyperuricemia * Often combined with colchicine * Used with anti-cancer drugs to prevent hyperuricemia * Adverse effects * Rash, fever, vasculitis * Hepatotoxicity, bone marror toxicity

Answer 128

* Inhibitor of xanthine oxidase * Uses * Gout attacks * Not recommended for treatment of asymptomatic hyperuricemia * Adverse effects * Rash, nausea, joint pain, liver function abnormalities

Answer 129

* Recombinant urate oxidase (uricase enzyme) * Uses * Decrease elevated urate levels in pediatric/adult cancer ptns * Efficacy can be reduced by presence of autoantibodies * Newer uricase agent - Pegloticase - is less immunogenic * Adverse Effects * Vomiting, fever, nausea, headache, abdominal pain, constipation, diarrhea, mucositis * Do not give to ptns with G6PD deficiency * Acute renal failure, anaphylaxis

Answer 130

* Probenecid, Lesinurad * MOA * Probenecid - inhibit reabsorption of urate by URAT-1 * Lesinurad - inhibit reabsorption of urate URAT-1 and OAT-4 transporters * Increase urate excretion, and increase uric acid concentration in urine * Adverse Effects * May cause attack of gout * May cause formation of intrarenal stones * GI irritation, peptic ulcers

Answer 131

* Decreases inflammation * Reduces pain in acute gout attacks * NSAIDs preferred over colchicine to combat gout * Preferred in elderly ptns w/ cardiac, renal or GI complications

Answer 132

* Inhibits xanthine oxidase enzyme * Xanthine oxidase catabolizes 6-MP to 6-thiouric acid (inactive) * Used to prevent and treat gout * Ptns taking antineoplastic drugs often generate large amounts of uric acid and must be co-treated with Allopurinol * The dose of mercaptopurine must be reduced by more than 1/2 when taken with allopurinol, b/c allopurinol's inhibition of mercaptopurine metabolism * No interaction with thioguanine