Chemotherapy past exam questions PDF

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Summary of past exam questions for Chemotherapy module including a table of which frequently came up and common themes...

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2018: 1. Discuss the mode of action of antifungals. - polyene (amphotericin): acts on cell membranes, affects permeability + transport functions by forming large pores, hydrophilic core creates transmembrane ion channel causing disturbed ion balance (↓ int K+), fungal selective, - echinocandins: inhibits 1,3-β-glucan synthesis for maintaining cell wall structure, cells lose integrity + lyse - azoles: broad, inhibit fungal cytochrome P450 3A enzyme lanosine 14α-demethylase, main sterol in cell membrane to convert lanosterol to ergosterol, ergosterol depletion alters membrane fluidity which interferes with membrane-associated enzymes (replication inhibition) - flucytosine: limited, converted to antimetabolite 5-fluorouracil, inhibits thymidylate synthetase (DNA synthesis) - terbinafine, naftifine: selectively inhibits squalene epoxidase, involved in ergosterol synthesis from squalene in cell wall, squalene accumulation is toxic (step before azoles)

2. Describe the MOA + basis for selective toxicity of antibacterial drugs targeting protein synthesis. - protein synthesis on ribosomes (E, P, A sites) - eukaryotic + prokaryotic gives ribosome selection (bacteria 50S + 30S, mammalian 60S + 40S), mostly bacteriostatic - mRNA forms template, tRNA transfers amino acids to ribosome, tRNA binds to A, transpeptidation (P site discharged), discharged tRNA translocated to E, repeat - pre-ribosomal inhibitors, mupirocin - mupirocin, isoleucyl tRNA synthetase substrate analogue, reversible, inhibits conversion of isoleucyl + tRNA - puromycin, causes premature termination, resembles amino acid end of tRNA - ribosomal inhibitors: early (tet, oxa), mid (amino, chlora, mac), late (fus) - tetracyclines, compete with tRNA for A, selectivity through AT selective uptake into prokaryotic cells, e.g minocycline - oxazolidinones - aminoglycosides, promote misreading of mRNA with abnormal codon, penetrates membrane through O2-dependent active transport e.g gentamicin - chloramphenicol, binds to L16 protein in 50S, inhibits peptidyl transferase + transpeptidation (1 aa transferred to another peptide) - macrolides, inhibits tRNA translocation, binds to 50S e.g erythromycin - adverse effects due to similar mitochondrial protein synthesis inhibition Selectivity Mupirocin Pro + euk structural synthetase

MOA Inhibits isoleucyl tRNA synthetase Substrate analogue

Uses -ve Staph + strep Topical

Tetra -cycline

differences Pro + euk uptake differences 30S

Oxazo 50S Amino -i/ycin

30S + 50S

Chlora Macro -lides

Fusidic

50S 50S

Pro + euk uptake differences

Prevent aminoacyl tRNA ribosome association Compete for A site Blocks subunit assembly, affects aminoacyl-tRNA binding in A site Promotes mRNA misreading with abnormal codon insertion Abnormal proteins cause membrane destabilisation Inhibits peptidyl transferase (transpeptidation) Binds 50S, blocks exit of growing peptides Premature peptidyl tRNA dissociation from P site Inhibits tRNA translocation Interferes with elongation factor G release

Broad Oral/IV/topical +ve IV/oral IM/IV Sepsis, endocarditis Broad Oral/IV/topical Azithromycin Erythromycin -ve

+ve Topical/oral/IV Staph

3. Discuss the role of hormones in the development of human cancers + how drugs have been developed to inhibit the growth. - hormone responsive (treatment) + dependent (removal) surgical or pharmacological - steroid-receptor complex binds in cell to chromatin, activates gene transcription - tamoxifen (anti-oestrogen), SERM (selective oestrogen receptor modulator), competes with steroid tor intracellular receptor, can stimulate lesions so limited use (5 years) - used with gonadotropin releasing hormone analogue in pre-menopause, aromatase inhibitors (anastrozole) used in post-menopause for peripheral oestrogen synthesis (liver, fat, breast) - flutamide, nilutamide (anti-androgens), competes with androgens - hormone resistance possible problem

2017: 1. Describe the influenza virus components that have been targeted by antiviral agents + explain how these drugs work. - virus -ve + segmented group, droplet + direct contact - 4 types A (17+, 8 segments, multiple animals), B (10+, 8 segments, humans), C (10+, 7 segments, human + pigs), D - HA haemagglutinin (membrane binding), NA neuraminidase (cleave sialic acid), M2 (H+ channel, 4) membrane proteins, + PA, PB1, PB2, NB nucleoproteins in matrix -viral HA binds to sialic acid receptor in host, endocytosis, endosome acidified by H+ influx (M2), endosome + matrix fusion releases RNP’s, NA promotes newly replicated virions escaping cell by breaking particle + sialic acid bond

- adamantanes (amantadine + rimantadine) M2, amantadine, efficacy, side effects - M2 mutations mean adamantanes no longer FDA approved - zanamivir + oseltamivir (Tamiflu) NA inhibitors, outcompetes sialic acid, virus contained, can’t infect other cells - given acyclovir - bicyclic pyrimidine nucleoside analogues (BCNA’s) e.g CF1743, 10000x > acyclovir potency, converted to diphosphate too (thymidine kinase) - opioid analgesics treat acute + persistent pain, bind brain receptors, controlled morphine/oxycodone release, adverse drowsiness, nausea, slow cognition - TCA’s block 5-HT + NE uptake transporter, ↑ []e enhances transmission

4. Compare + contrast the antibacterial MOA of β-lactam antibiotics + vancomycin . ^ 2011: 1. Identify steps in the cell cycle that form targets for anti-cancer drug therapy, giving examples of clinical drugs that target cycling cancer cells. ^

2. Describe the MOA + basis for selective toxicity of antibacterial drugs targeting protein synthesis

^ 3. All current antifungal drugs target the fungal cell membrane/cell wall, referencing MOA of named drugs discuss this. ^ 4. Describe how the influenza ion channel is targeted for antiviral chemotherapy using examples. - ^ M2 2010: 1. Explain how the antimetabolites used in cancer chemotherapy block cell division. - S phase, DNA/RNA synthesis - AT, inhibits dihydrofolate reductase (DHFR) - leucovorin rescue, converted to N5, N10-methylene-FH4 + bypasses inhibited reductase - e.g methotrexate, structurally related to folic acid, retained as MTX polyglutamate - acute lymphoblastic leukaemia, breast + neck cancer

2. Compare + contrast the MOA of β-lactam antibiotics + vancomycin. ^ 3. Discuss the chemotherapy of fungal infections ^ 4. Describe the development + applications of antiviral chemotherapy by targeting viroporins. - #######

2009: 1. Describe the MOA of 4 named anti-cancer drugs of different mechanisms. ^ 2. Discuss the MOA of β-lactam antibiotics. ^ 3. Account for the antiviral effects of acyclovir, saquinavir + zidovudine, + outline therapeutic uses. ####### - acyclovir, vDNA polymerase inhibitor, guanosine derivative, herpes, suppressive therapy - viral thymidine kinase converts to monophosphate, then to triphosphate (2 cellular kinases) incorporated + terminates chain, stops replication - saquinavir, protease inhibitor, HIV, usually in combination with retrovirals - viral proteases converts inert polyproteins from mRNA into structure/function proteins, inhibitor binds to cleavage site, stops viral protein processing

- zidovudine, nucleoside analogue, HIV (prolongs life + diminishes dementia) - phosphorylated to 5’-triphosphate derivatives, competes for proviral DNA synthesis by inhibiting reverse transcriptase, incorporation into DNA chain terminates it, stops replication 4. List the characteristics of an ideal chemotherapeutic agent, how to the properties of amphotericin, ivermectin + chloroquine match these. - non-toxic (selective), pharmacokinetics (ADME), large therapeutic window, low resistance, low costs - amphotericin (polyene), Aspergillus + Candida, good selectivity from ergosterol targeting (rarely mammalian + no bacteria binding) - ivermectin (antiparasitic), broad, filariasis, well tolerated - chloroquine, Amphoterici n (polyene)

PK Slow IV reduces effects Highly protein-bound Penetrates poorly Kidney excretion slow

Ivermectin

Adverse effects Rigors, child, headache (IV) Hypotension Anaphylactoid Renal toxicity Rash + itching

Resistance

Chloroquine 2008: 1. Discuss the selective mechanisms of targeted anti-cancer drugs Gleevec, Avastin, Iressa, + Herceptin. - Gleevec/imatinib: BCR-ABL inhibitor, fusion of 2 genes (22+9) from chromosomal translocation in chronic myelogenous leukaemia, tyrosine kinase activity, - Avastin/bevacizumab: inhibits VEGF (vascular endothelial growth factor), blocks angiogenesis - colon cancer + 5-fluouracil - Iressa/gefitinib: tyrosine kinase inhibitor, blocks cell growth signals, blocks tyrosine kinase intracellular domain in EGF receptors - non small cell lung cancer that spread - Herceptin/trastuzumab: monoclonal antibody, inhibits HER2 (human epidermal growth factor rec 2) extracellular domain, high levels cause proliferation - breast cancers with no α-oestrogen or progesterone receptor expressed, when tamoxifen not responsive, oesophageal + stomach cancer

2. Describe the MOA, therapeutic uses + unwanted effects of the 3 different classes of antifungal drugs. ^ 3. Discuss the chemotherapy of malaria.

4. Describe how drugs interfere with bacterial protein synthesis with examples.

^ 2018

2017

2014

2013

2012

2011

2010

2009

2008

Antifungals MOA

Antibacterial (protein synthesis) β-lactam + glycopeptides

Hormones in cancer + drug targets Influenza + Cytotoxic drugs antivirals in membrane + cancer Antifungals Influenza + Anti-cancer MOA antivirals targets + cell cycle Influenza, HIV + antivirals Antibacterial adamantanes, MOA drugs (cell neuraminidase envelope) Anticancer, Antifungals Herpes (HZ) + nucleotide + (polyene, fluc, antivirals DNA synthesis azoles) MOA Anticancer + Antibacterial Antifungals cell cycle drugs (protein (membrane/wall) synthesis) MOA Cancer β-lactam + Fungal antimetabolites vancomycin chemotherapy MOA Anticancer β-lactam MOA Antiviral MOA acyclovir, saquinavir Anticancer Antifungals, Malaria Gleevec, MOA, chemotherapy therapeutic, Avastin, adverse Herceptin

Genital herpes

Oncogenes + anticancer β-lactam + vancomycin MOA Influenza + antivirals Antivirals + viroporins Amphotericin, ivermectin, chloroquine Antibacterial (protein synthesis)

Schizophrenia - +ve behaviour + Opioids - neuropeptide transmitter, bind to opium post-syn receptors, produces morphine-like effects, free OH in benzene facilitates opioid activity -3r

Migraine - idiopathic nerve transm

GABA - main inhibitory NT in brain, formed from glutamate from glutamic acid decarboxylase - A ligand- B:...