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Pharmacology Jeopardy Block 2 - Part I Peter O. Beaumont, M.Sc. (Pharm) St. Vinnie’s Fall 2000 Antibiotics It is thought that a cell Tx with penicillin may have to produce these in order to be bactericidal What are… Autolysins – This is part of the reasoning why you should not mix tetracyclines with cell wall synthesis inhibitors The estimated rate of resistance of S. aureus to penicillin G What is… 90% – You should always be cognizant of this when prescribing antibiotics for Staph infections This ‘prophylactic’ acronym reminds you what drugs to use for many staph infections What is… CONDoM – recall, all the penicillins with ‘ox’ in them can be taken orally. – Naficillin, can be oral, but abs is variable – Methicilin is definitely not oral For P. aeruginosa, choose one of these penicillins What are… Mezlocillin Carbenicillin Azlocillin Ticarcillin Piperacillin This penicillin is cleared by the kidney, but spends time in the bile, making it useful against this ‘fishy’ organism What is… Ampicillin & Salmonella (Carrier state) This aminopenicillin is not affected by food when taken orally What is… Amoxicillin Penicillin G does not penetrate well into these 3 organs What are… The eye, prostate and meninges (uninflammed) The only penicillin to be used in patients with Renal Failure What is… Naficillin – It is the only one cleared mainly be the liver Match the beta-lactam ADR neutropenia hepatitis nephritis allergic rash in Mono Naficillin Oxacillin Methicillin Ampicillin Fever chills, rigors and arthralgia due to release of spirochete toxins What is… The Herxheimer Reaction – Occurs with most spirochetes, and is independent of the antibiotic used While 1st-Gen Cephs are known for their activity for G-pos, organisms they are still active against these G-negs... What is… • Proteus mirabilis • Enterobacter • E. coli • Klebsiella pneumoia • Mloraxlla catarrhalis These drugs have in common the side effect of hypoprothombinemia and a disulfiram-like reaction What are… Cefoperazone, Moxolactam and Cefomandole – 3rd, 3rd and 2nd gen agents The main difference between 3rd and 4th-Gen cephs.., What is… more resistance to beta-lactamase – Especially chromosomal lactamase produced by Enterobacter Type of superinfection likely in 3rd-Gen cephs What is… Gram-positive organisms – recall, as you move from 1st to 3rd Gen, there is more G-neg activity and less G-pos activity Don’t ask me why, but this common lab test may become positive with the use of cephalosporins What is… Urine test for glucose – Apparently, this is for all classes of cephs. The First Gen Cephs Parenteral Oral Cefazolin (Ancef™) Cephalothin Cephapirin Cephradine Cephalexin (Keflex™) Cefadroxil Cephadrine Radical Zoltan lothes rox-star pirsonalities who drive lexuses The spectrum of this class of betalactams is just like the aminoglycosides What are… Monobactams – Active against G-negs – No activity against G-pos or anaerobes – Aztreonam is the only drug in the class This beta-lactam has the broadest spectrum of all and greatest resistance to lactamase What is… Imipenem – Think Omni-potent imipenem – Cilastin makes it resistant to dihydropeptidase in the kidney The only iv drug studied that is limited solely to G-pos organisms What is… Vancomycin – iv for Tx of MRSA (usually with an aminoglycoside) – po for Tx of C.difficile – one exception is G-neg Flavobacterium - but I don’t think we studied it This antibiotic works only in the periplasmic space What is… Bacitracin – Interferes with cycling of the lipid transporter Bactoprenol – too toxic for systemic use – G-pos organisms only Inhibits the conversion of L-ala to D-ala What is… Cycloserine – Inhibits alanine racemase – almost exclusively used as 2nd line Tx for TB due to toxicity – “Psycho-serine” Sulfas used in bowel-prep, based on the absorption profile What are… Phthalylsulfathiazole Succinylsulfathizole and Sulfaquanine – Neomycin is also effective in this regard Acidity in the urine causes precipitation of this drug class What are… Sulfa drugs Mechanisms of resistance to sulfa drugs... What are… • decreased affinity for dihydropteroate synthase • overproductoin of PABA • increased acetylation – Plasmid mediate The crossing of unconjugated bilirubin into the CNS in newborns What is… kernicterus – Occurs in sulfonamides and other drugs that are normally highly bound to albumin in adults This drug is supposed to release formaldehyde as part of its mechanism of action What is… methanamine mandelate – forms insoluble complex with sulfas – not active against Proteus due to urea splitting activity - pH must be below 5.5 With this drug... your patient might say, “Thanks Doc, I don’t have to pee so often, but it sure comes out funny looking” What is… phenazopyridine – urinary anaesthetic – produces red-orange urine – no antibacterial effect on its own The common ADR of Trimethoprim, pyrimethamine, and sulfas What is… dose-dependent bone marrow depression due to lack of folate The enzymes inhibited by sulfa drugs, pyrimethamine, Trimethoprim and Methotrexate What are… Dihydropteroate synthase, parasitic, bacterial and mammalian DHFR, respectively At therapeutic, bacteriostatic concentrations, the degree of toxicity in Fast acetylators What is… potentially more – fast acetylators have fewer incidences of immune mediated ADRs (SJS, SLE, etc.) – acetylation blocks antibacterial activity, but not the other toxicities. To achieve Tx levels, you need more drug in these patients! DOC in AIDS PCP What is… Sulfmethoxazole Trimethoprim – Also effective in acute toxoplasmosis, and malaria but pyrimethamine might be better if that is all you are treating These drugs block relaxation of positively supercoiled DNA What are… Fluoroquinolones – effective in UTI caused by MDR Psuedomonas – Concentrations higher in prostate, kidney, bile and stool This drug is only good for UTI and specifically not pseudomonas or proteus What is… Nitrofurantoin – No systemic activity – bacteria reduce the agent to reactive intermediate, but require pH below 5.5 Bacteriostatic drug working at the 30S subunit What is… tetracyclines – Aminoglycosides also work at the 30S subunit, but they are bacteriostatic The only important cause of atypical CAP, not covered by tetracyclines What is… Legionella – Tetracyclines are active against Mycoplasma & Chlamydia – Also includes: G-pos, G-neg, and Spirochetes Two agents used to Tx SIADH What are… demeclocycline and + Li – Impt ADR of demeclocycline is photosensitivity Renal tubular acidosis, aminoaciduria, glycosuria, proteinuria, polydipsia What is… Fanconi Syndrome – impt ADR from ingesting OUTDATED (expired) tetracyclines The two main antibiotics used in the Tx of Acne What are… Tetracyclines and Clindamycin – Tretinoin (Accutane™) is used too, but it is not an antibiotic, it is a retinoid – Some macrolides and sulfas are also used occasionally Broad spectrum, bacteriostatic agent working at the 50S subunit What is… Chloramphenicol – Inhibits peptidyl transferase – Macrolides also work at the 50S, but according to Dr. Reddy they are not broad spectrum – Bacteroides are highly susceptible Impt dose-related ADR of Chloramphenicol seen in all age groups What is… Bone Marrow Suppression – Aplastic anaemia is idiosyncratic – Grey-baby syndrome is only in newborns Generally, a substitute for Pen G (in allergy), and a DOC for atypical CAP What is… Erythromycin –I Chief reason for discontinuance of erythromycin What is… Gastrointestinal intolerance – Direct stimulation of gastric motility.This is a significant problem, albeit with minimal morbidity – incidence of liver tox is increased in pregnancy Increased acid stability, less GIT upset and activity agasinst Mavium, leprae & T.gondii What is… Clarithromycin – also has a longer T1/2 than erythromycin – Azithromycin adds an even longer T1/2, permitting once-daily dosing Same mechanism of action as the macrolides, but an entirely different structure What is… Clindamycin – Main indication is severe Bacteroides infection – high incidence of resistance in C. difficile --> Pseudomembranous colitis – Supplanted Erythro in prophylaxis of endocarditis peri-operatively Interferes with 30S ribosome and causes misreading of mRNA What are… Aminoglycosides – Main clinical indication in Tx aerobic, G-neg organisms (PPEEKS) – No activity in anaerobes – Synergy with cell-wall agents Aminoglycoside without activity for G-neg rods What is… Streptomycin – Ancient Drug for ancient bug – Plague, TB and tularemia Aminoglycoside used as 2nd line Tx in Pen resistant gonorrhea What is… Spectinomycin – Use a ‘speculum’ before you Rx spectinomycin – Not ototoxic or nephrotoxic like other aminoglycosides Indicated in pre-op bowel prep and hepatic coma What is… Neomycin – Sterilizes the bowel, eliminating bacterial source of ammonia in liver - which exacerbates liver failure Use this aminoglycoside for parasite infection What is… Paromycin – Too toxic for systemic use – Given po as a luminal amebicidial agent – crypto, visceral leish, and cestodes The other major side effect everyone forgets about with aminoglycosides What is… NMJ blockade – curare-like, reversible with neostigmine and Ca gluconate Topical agents with G-neg activity, that interact with membrane phospholipids What are… polymixins – commonly used in ophthalmic and otic preparations – combined with Bacitracin to cover G-pos or neomycin for additional G-neg Antifungals These 2 drugs…. Are antifungals that both have efficacy against cryptococus neoformans meningitis and are given p.o. What are… Flucytosine and Fluconazole – if you said Amphotericin B, remember, it is only given iv! The amphipathic nature of these polyene drugs…. Allow them to create pores in fungal membranes What are… Amphotericin B and Nystatin – both of these agents bind to ergosterol and are amphipathic (a hydophobic side and a hydrophilic side) - wanna guess where amphoteracin got its name? These 4 drugs…. All affect microtubule formation as part of their mechanism of action What are… Colchicine Griseofulvin Vincristine Albendazole (et al) Better take this drug with a Big Mac, fries and a shake, but not your sleeping aids What is… Griseofulvin – absorption increased by fat, and decreased by barbiturates Drug A inhibits the absorption of B, but B inhibits the metabolism of A. Hint: ulcers and fungi What are… A: Cimetidine B: Ketoconazole – ketoconazole requires and acid environment for absorption and competes for CYP3A4 with cimetidine These drugs…. Provide induction and maintenance Tx of Cryptococus neoformans, respectively What are… Amphotericin B and fluconazole This drug…. Is used for topical Tx of Candida, but not dermatophytes What is… Nystatin – only miconazole, clotrimazole and econazole affect dermatophytes topically – Giseofulvin gets, them, but does so systemically This antifungal…. Plus the right bacteria, will depress your bone marrow What is… Flucytosine – Some intestinal bacteria will deaminate 5-fluorocytosine to 5fluorouracil, an effective antineoplastic agent in mammalian cells CANCER CHEMOTHERAPY If a drug killed 99.99% of all cells in a 100g tumour; this many cells would remain What is… 7 10 – A 100 g tumour = ~1011 cells, there fore, you would lose 4-orders of magnitude An effective route of admin for mechlorethamine, but not cyclophosphamide What is… intra-arterial – Cyclophosphamide requires metabolic activation By definition, these antineoplastics work best in the M-phase of the cell cycle What are… Vinca Alkaloids and paclitaxel – Both affect microtubule assembly and hence the mitotic spindle Decreasing order of toxicity of the 3 main alkylating agents in the handout What are… mechlorethamine > cyclophosphamide > chlorambucil – Chlorambucil is safe enough to be used as an immunosuppressant This metabolite of Cyclophosphamide is toxic to the bladder What is… acrolein – Causes hemorrhagic cystitis and is Tx with sulfhydryl agents like MESNA (2-mercapotethane sulfate) – Considered most useful alkylating agent This class of alkylating agents have better efficacy in CNS tumours What are… Nitrosoureas – Carmustine (BCNU) and Lomustine (CCNU) are more lipophilic than the other agents This alkylating agent is said to have efficacy in suppressing bone marrow prior to transplant What is… Busulfan If in doubt, the limiting toxicity of any anti-CA agent is: What is… Bone Marrow Suppression – However, there are some very notable exceptions to follow….. An important result of mass destruction of CA cells. Hint: think DNA breakdown products What is… Hyperuricemia – release of purines from damaged cells leads to increases in uric acid after metabolism by xanthine oxidase This agent acts like an alkylating agent, but is structurally dissimilar. What is… Cisplatin or Carboplatin The limiting toxicity of cisplatin, which is reduced by IV fluids and mannitol What is… nephrotoxicity – ototoxicity and peripheral neuropathy are not affected By decreasing protein binding, this happens quicker in Caroplatin and hence returns the limiting toxicity back to bone marrow What is… renal elimination – Carboplatin is used in many patients who cannot tolerate the nephrotoxicity of cisplatin These 4 agents are by definition Sphase specific What are… 5-FU, Methotrexate, mercaptopurine & Ara-C – These agents are either antimetabolites, or interfere with purine or pyrimadine synthesis Inhibition of this enzyme leads to lack of dTMP and reduced components for purine synthesis What is… DHFR This drugs inhibits the previous enzyme What is… Methotrexate This agent is regarded by many as having the broadest anticancer spectrum What is… Doxorubicin – Daunorubicin is only used against leukemias Mechanisms of action of Doxorubicin What are… Intercalatoin of DNA, effects on Topo II, toxic free radical – Partly cell-cycle specific, partly not – H. Baer packet says not This agent, combined with etoposide and cisplatin is effective in Testicular CA What is… Bleomycin – Significant lung toxicity Dose-limiting toxicity of doxorubicin What is… cardiomyopathy – Dose-related, occurs beyond (cummulative) 500mg/m2 Mechanism of the podophyllotoxins What is… inhibit Topo II – Cause DNA strand breaks – work in late 2-G2 – Etoposide & Teniposide GASTROINTESTINAL PHARMCOLOGY The general Tx regimen for established H.pylori mediated PUD What is… PPI or H2 or bismuth + Metrondazole & 2nd Antibiotic selectively binds the ulcer AND may have antibacterial effects What is… Bismuth – ADR: black mouth and stool, salicylism This H2 receptor antagonist prototype drug affects the metabolism of many other drugs What is… Cimetidine – Competatively inhibits P450 – Cause estrogenic effects The difference in efficacy among the newer H2 antagonist What is… Essentially none – Longer lasting, few SE, more $$ The active metabolite of this class of “antacids” irreversibly inhibits the H/K ATPase What are… proton pump inhibitors – Omeprazole and lansoprazole – effect remains until new pump is synthesised – Generally well tolerated analogue 2 What is… misoprostol 3 effects of misoprostol What are… inhibit acid secretion, stimulate bicarb secretion, increase mucus secretion Major contraindication for misoprostol What is… pregnancy – pro-abortificant actions This agent preferentially binds the ulcer base to protect it What is… Sucralfate – absorbs acid, pepsin and bile Common ingredient of Nytol, Dramamine and Dimetap What is… Dimenhydrinate – 1st Generation H1 blockers – block both H1 and ACH receptors to produce anti-emtic effect One of the original “truth serums”, now used as a patch to prevent sea sickness What is… Scopolamine – Primary action is Anti-cholinergic effect on CTZ zone – major SE of sedation – Benztropine (Cogentin) and cyclizine are congeners These agents should be “high” on your list of adjuncts in Cancer Tx What are… Cannabinoids – Dronabinol and nabilone (derivatives of tetrahydrocannabinol) – You can figure out the SE Predictable SE of Prochlorperazine & promethazine (Compazine and Phergan for you clinicians out there) What is… Parkinsonism – Upsets the DA - ACh balancein the basal ganglia Treatment of the SE of above with this, actually enhances the anti-emetic effect! What is… Diphenhydramine – Additional anti-ACh effect restores the ratio in the BG – benztropine may also be commonly used Anti-serotonin agent with good efficacy in N&V associated with Chemo and Rad What is… Ondansetron – blocks the 5-HT3 receptor (which is the only ion channel of the HT receptor group) Amazing combo of CNS anti-emetic and gut promotility make this agent very useful What is… Metoclopromide – Anti-DA and anti-5-HT3 in CNS – muscarinic agonist in the GIT SE of the above agent… based on mechanism of action What is… Also causes Parkinsonism – Specific effect mentioned in class is occulogyral crisis Medical reason for not using mineral oil laxatives What is… fat soluble vit dificiency and lipid pneumonitis if aspirated Social reason to not use mineral oil laxatives What is… They leak out you bum! Mech of Act of Exlax, etc. What is… irritant to Auerbach’s plexus in the colon – phenolphthalein turns stools pink remember CHEM 101? – May cause post-use constipation These agents have a positive effect on the G.I. Ward, that is a SE on the orthopedics ward What are… Opiods – Diphenoxylate is a weak analogue of meperidine (Demerol) – direct action on the ENS: fewer propulsive waves This agent is commonly added to anti-diarrhea opiod preparations What is… Atropine – unpleasant CNS SE limit addictive potential of diphenoxylate This anti-diarrheal requires no addition of atropine What is… Loperamide – Does not cross the BBB in significant amounts Class of agents used to decrease GIT tone and motility What are… Anti-cholinergics – Dicyclomine mentioned in the notes – Reportedly, has less anti-ACh side effects than atropine END of Part I