Pharmacology Review: Antibiotics. Presented by: A Nelson Avery, MD

Transcription

1 Pharmacology Review: Antibiotics Presented by: A Nelson Avery, MD Board Certified in Toxicology, Preventive Medicine and Internal Medicine Clinical Professor and Director Preventive Medicine Residency Program navery@medicine.tamhsc.edu

2 Outline Antibacterial agents: Penicillins & Cephalosporins Carbapenems Vancomycin Aminoglycosides Streptogramins, Linezolid Tetracyclines Macrolides Chloramphenicol Clindamycin Sulfonamides Fluoroquinolones Metronidazole Antituberculin agents: INH Rifampin Other TB drugs Dapsone Antifungal agents: Amphotericin B Nystatin Azole antifungals Flucytosine Terbinafine Griseofulvin Antimalarial drugs: Quinine Chloroquine Other antimalarial drugs Antiviral drugs: Amantadine, Rimantadine Oseltamavir, Zanatamavir Ribavirin NRTIs NNRTIs Protease inhibitors Other HIV Drugs CMV agents HSV agents A Nelson Avery, MD 2

3 Antibacterial Agents A Nelson Avery, MD 3

4 Antimicrobial Mechanism Inhibitors of cell wall synthesis: penicillins, cephalosporins, carbapenems, vancomycin Inhibitors of protein synthesis by ribosomal subunit binding: 30S: aminoglycosides, tetracycline 50S: chloramphenicol, erythromycin, clindamycin, streptogramins & linezolid Inhibitors of folic acid synthesis: sulfonamides & trimethoprim Inhibitors of nucleic acid synthesis: fluoroquinolones A Nelson Avery, MD 4

5 Penicillins: Mechanism Bind to penicillin binding proteins on cytoplasmic membranes à inhibition of transpeptidase enzymes involved in crosslinking peptidoglycan chains (necessary for the final step in cell wall synthesis). A Nelson Avery, MD 5

6 Penicillin G Degraded by beta-lactamases (penicillinases), which are secreted by resistant bacteria Inactivated by acid in stomach Penicillin VK is acid resistant Actively secreted in urine A Nelson Avery, MD 6

7 Antistaphylococcal Penicillins (e.g., methicillin, oxacillin, nafcillin, dicloxacillin) Resistant to beta-lactamases useful in treating Staphylococcus aureus (but not MRSA strains) Other agents used for MRSA (see below): Vancomycin Linezolid, Quinupristin + dalfopristin, Sulfamethoxazole/ trimethoprim (Bactrim ) A Nelson Avery, MD 7

8 Other Penicillins Broad spectrum penicillins (e.g., ampicillin, amoxicillin) Clavulenic acid and sulbactam are added to inhibit beta-lactamases Antipseudomonal penicillins (e.g., carbenicillin, ticarcillin, mezlocillin, piperacillin) A Nelson Avery, MD 8

9 Penicillins: Toxicity Seizures (from high doses IV) Hypersensitivity (5%) & anaphylaxis (type 1 reaction, IgE mediated) Serum sickness (7-10 days after start drug, with fever, arthritis, urticaria, lymphadenopathy, edema) Interstitial nephritis (é BUN, fever, rash, é eosinophils), seen with methicillin and others Excess Na+ load (ticarcillin) A Nelson Avery, MD 9

10 Penicillins: Toxicity (cont.) Rash (most common with ampicillin in ~2/3 of patients with mononucleosis) é LFTs (oxacillin, nafcillin, carbenicillin) Blood related: Immune hemolytic anemia/ bone marrow suppression ê Neutrophils (oxacillin, nafcillin) Platelet dysfunction (carbenicillin, ticarcillin) and ê platelet count A Nelson Avery, MD 10

11 Penicillins: Interactions Carbenicillin and ticarcillin à é risk to bleed on oral anticoagulants because of platelet dysfunction High doses of penicillins may inactivate aminoglycosides Salicylates (aspirin) compete with penicillin G for renal excretion à é half-life and blood level of penicillin Probenecid inhibits renal tubular secretion of penicillins à é blood level Allopurinol à predispose to ampicillin rash A Nelson Avery, MD 11

12 Cephalosporins Have a beta-lactam ring, but are not a penicillin class drug Work in a similar mode to penicillins, but are more resistant to beta-lactamases Most are eliminated by active tubular secretion;; cefoperazone and ceftriaxone are eliminated in bile 1 st and 2 nd generation do not enter the CNS;; for meningitis can use 3 rd generation or cefuroxime (2 nd gen.) A Nelson Avery, MD 12

13 Cephalosporins: Toxicity Cross reaction to cephalosporins can occur in penicillin-sensitive persons Seizures in high dose Overgrowth of C. difficile à antibiotic associated colitis (pseudo-membranous colitis) Coagulation defects (ê vitamin K dependent factors;; associated with NMTT (n-methyl thiotetrazole) side chain;; moxalactam, cefamandole, cefotetan, cefoperazone) Disulfiram-like reaction with alcohol: cefamandole and cefoperazone A Nelson Avery, MD 13

14 Carbapenems: Imipenem Used for penicillin resistant gram (-) and (+) bacteria Given with cilastatin: Increases the spectrum Protects kidneys from toxic effects Keeps kidneys from inactivating it with dihydropeptidase Toxicity: seizures (in 5% after 7 days), phlebitis Other agents: meropenem, ertapenem A Nelson Avery, MD 14

15 Vancomycin Glycoprotein produced by a streptomyces Inhibits glycosylation by binding to the terminus of the pentapeptide chains of peptidoglycans Used for MRSA, and orally for C. difficile antibiotic-associated colitis 90% excreted by the kidneys (ê dose with renal failure) A Nelson Avery, MD 15

16 Vancomycin: Toxicity Nephrotoxicity Direct ototoxicity à hearing loss Red man syndrome: rapid infusion à histamine release à fever, chills, paresthesias, erythema on neck, ê BP (also seen with rifampin) A Nelson Avery, MD 16

17 Aminoglycosides Agents: gentamicin, neomycin, tobramycin, streptomycin, amikacin Bactericidal: inhibit formation of initiation complex and cause misreading of mrna Require O 2 for uptake, so do not use with anaerobes Eliminated entirely by glomerular filtration (ê dose with renal failure) May be inactivated by high dose penicillin Resistance occurs via plasmid-mediated formation of inactivating transferases A Nelson Avery, MD 17

18 Aminoglycosides: Toxicity Ototoxic (VIII nerve damage) à hearing loss, ataxia (streptomycin is vestibuletoxic);; é ear toxicity with loop diuretics (e.g., furosemide) Nephrotoxic (acute tubular necrosis) Neuromuscular blockade (inhibits ACh release) seen with myasthenia gravis or receiving neuromuscular blocking agents (with anesthesia) A Nelson Avery, MD 18

19 Streptogramins & Linezolid Streptogramins: quinupristin-dalfopristin is bactericidal, binding to the 50S ribosomal subunit, blocking extrusion of nascent polypeptides, and cause misreading of mrna;; used for MRSA and VRE bacteremia;; à ê P450 enzymes Linezolid (an oxazolidinone) is bacteriostatic, binds to 50S subunit to block initiation;; used for MRSA A Nelson Avery, MD 19

20 Tetracyclines Agents: tetracycline, minocycline, doxycycline, demeclocycline Bacteriostatic Bind to 30S ribosomal subunit, and blocks protein synthesis by blocking aminoacyltrna access to mrna (so it is catabolic) Used in treating rickettsial infections (e.g., Rocky Mountain spotted fever), Lyme disease, mycoplasmal and chlamydial infections A Nelson Avery, MD 20

21 Tetracyclines: Toxicity Yellow-gray-brown discoloration of teeth if exposed in last half of pregnancy or thru age 8 (until adult teeth come in) Photosensitivity Catabolic (anti-metabolic) à é BUN GI irritation and hepatotoxic A Nelson Avery, MD 21

22 Tetracyclines: Interactions ê Absorption of tetracycline caused by: milk, aluminum antacids, NaHCO 3, Ca ++ and Mg ++ salts, iron Demeclocycline used to treat severe hyponatremia (SIADH) by antagonizing the effect of ADH (i.e., it causes a relative diabetes insipidus) A Nelson Avery, MD 22

23 Macrolides Agents: erythromycin, clarithromycin, azithromycin Bacteriostatic Bind to 50S ribosomal subunit, block peptidyl transferase and prevent translocation step in protein synthesis Widely used in patients who are allergic to penicillin (and other beta-lactam antibiotics) Used for mycoplasma, Legionella A Nelson Avery, MD 23

24 Macrolides: Toxicity Activate motilin (GI hormone) à nausea, vomiting in ~25% Cholestatic hepatitis (erythromycin estolate) Hypersensitivity reaction (rash, fever, eosinophilia) Interactions: à ê P-450 enzymes à é levels of: theophylline, warfarin, phenytoin, carbamazepine, quinidine, protease inhibitors à é digoxin absorption by change in intestinal flora A Nelson Avery, MD 24

25 Chloramphenicol Broad-spectrum antibiotic that binds to 50S ribosomal subunit, which inhibits elongation of polypeptide chains (blocks peptidyl transferase);; bacteriostatic Can be used to treat beta-lactamase (+) bacteria Resistant bacteria have a plasmid-encoded acetyltransferase, an inactivating enzyme Used clinically to treat meningitis A Nelson Avery, MD 25

26 Chloramphenicol: Toxicity Aplastic anemia (unpredictable, idiosyncratic, irreversible) Allergic marrow toxicity (reversible): ê platelets, anemia, ê WBC Gray baby syndrome in neonates (lack liver glucuronyl transferase) Interactions: à ê P-450 à é phenytoin à phenytoin toxicity é oral anticoagulants à é protime & bleeding é oral hypoglycemics à hypoglycemia A Nelson Avery, MD 26

27 Clindamycin Bacteriostatic Binds 50S ribosomal subunit Use to treat anaerobic infections Toxicity: C. difficile colitis, (+) fecal WBC in 50%, pseudomembranes, (+) toxin in stool is the best dx test) Hypersensitivity reactions: skin rash, urticaria A Nelson Avery, MD 27

28 Bacteriostatic Sulfonamides Most frequently used as a combination of sulfamethoxazole (inhibits dihydropteroate synthase) with trimethoprim (which inhibits dihydrofolate reductase) Together they cause a sequential blockade of tetrahydrofolic acid synthesis inside the bacteria There are a lot of non-antibiotic sulfa drugs: furosemide, acetazolamide, thiazides, sulfonylureas, sulfasalazine, probenecid, celecoxib A Nelson Avery, MD 28

29 Sulfonamides: Toxicity Hemolysis (with G6PD deficiency) Aplastic anemia (direct toxic effect);; megaloblastic anemia Toxic epidermal necrosis, Stevens Johnson syndrome;; photosensitivity Hepatic necrosis Interactions: à ê P-450 (for effects, see chloramphenicol above) A Nelson Avery, MD 29

30 Fluoroquinolones Agents: ciprofloxacin, norfloxacin, ofloxacin, etc. (all end in floxacin) Bactericidal: inhibits topoisomerase II (= DNA gyrase) à blocks the relaxation of supercoiled DNA and topoisomerase IV (prevents separation of replicated DNA) à inhibits DNA synthesis Can use for gonorrhea and GI / GU infections A Nelson Avery, MD 30

31 Fluoroquinolones: Toxicity Hypersensitivity ê Platelets, ê WBC GI sx Renal failure, hematuria Contraindicated in pregnant women and in children because possible cartilage damage Tendonitis and tendon rupture in adults Lactic acidosis Blocks GABA receptors à seizures, psychosis A Nelson Avery, MD 31

32 Metronidazole Bactericidal Used for amebiasis, giardiasis, anaerobes, trichomonas, gardnerella Used with bismuth + an antibiotic (e.g., amoxicillin, tetracycline, clarithromycin) for triple therapy for H. pylori infection A Nelson Avery, MD 32

33 Metronidazole: Toxicity Disulfiram-type reaction with alcohol (flushing) Neurological sx: seizures, peripheral neuropathy, dizziness, vertigo Nausea, vomiting, diarrhea Interactions: à ê P-450 à é levels of warfarin à ê prothrombin & é PT A Nelson Avery, MD 33

34 Antituberculin Agents A Nelson Avery, MD 34

35 Isoniazid (INH) INH = isonicotinic hydrazide Used to treat tuberculosis;; decreases synthesis of mycolic acids in mycobacterium Fast acetylation (by the enzyme n-acetyl-transferase) in Orientals à ½ the normal concentration found in Caucasians with slow acetylation. Resistance involves deletions in the katg gene and inha gene. A Nelson Avery, MD 35

36 Isoniazid (INH): Toxicity Clinically relevant hepatitis in 0.1% of persons receiving INH (caused by metabolite acetylhydrazine);; death rate 0.001% Risks for hepatitis include: older, alcohol, coadministration of rifampin, (acetylator status makes no difference in risk) Blood issues: agranulocytosis, é eosinophils, ê platelets, anemia;; hemolysis with G6PD deficiency SLE-like syndrome A Nelson Avery, MD 36

37 Isoniazid (INH): Toxicity INH inhibits pyridoxine kinase à ê formation of active form of vitamin B 6 (pyridoxal phosphate) à ê synthesis of GABA in brain à seizures. Peripheral neuropathy (from B 6 interference) is the most common neurological manifestation;; may be prevented with low doses of pyridoxine (vitamin B 6 ) A Nelson Avery, MD 37

38 Isoniazid (INH): Overdose Triad of overdose : Repetitive seizures (tonic clonic), refractory to usual anticonvulsants it is the most common cause of drug-induced seizures in US treated with pyridoxine (B 6 ) Metabolic acidosis (anion gap) refractory to NaHCO 3 Coma A Nelson Avery, MD 38

39 Rifampin Treatment for tuberculosis Antibiotic binds to beta-subunit of DNAdependent RNA polymerase, thus prevents RNA synthesis Has enterohepatic circulation Used for tuberculosis, leprosy, meningococcal exposure or carriers (but not for treatment of acute meningococcal infections) Second-line rifamycins: rifabutin, rifapentine, rifaximin A Nelson Avery, MD 39

40 Hepatotoxicity Rifampin: Toxicity Flu-like syndrome Cutaneous syndrome (flushing, pruritus, rash, red eyes) Red-orange color of secretions;; will even tint contact lenses Interactions: Potent inducer of cytochrome P-450 à ê levels of many drugs, including coumadin, oral hypoglycemics, theophylline, anticonvulsants, oral contraceptives A Nelson Avery, MD 40

41 Other Agents for TB Ethambutol Inhibits the synthesis of arabinogalactan, a component of mycobacterial cell walls Toxicity: retrobulbar neuritis, reduction in red-green visual acuity;; hyperuricemia Pyrazinamide Toxicity: polyarthralgias, hyperuricemia, phototoxicity, exacerbation of porphyria A Nelson Avery, MD 41

42 Dapsone Treatment for leprosy and for pneumocystis pneumonia Toxicity: GI irritation, skin rash, met-hgb, hemolysis with G6PD deficiency, agranulocytosis A Nelson Avery, MD 42

43 Antifungal Agents A Nelson Avery, MD 43

44 Amphotericin B Polyene antifungal that binds with membrane ergosterol to produce leaky pores Half-life is ~24 hours not affected by renal failure, but most will develop ê renal function while on treatment Given intravenously, or intrathecally for fungal meningitis (does not cross bloodbrain barrier) A Nelson Avery, MD 44

45 Amphotericin B: Toxicity Nausea & vomiting, hepatotoxicity Azotemia in 80% (minimize with infusion of normal saline) Renal tubular acidosis, ê K+ Thrombophlebitis Fever & chills (control with infusion of diphenhydramine and acetaminophen) Arrhythmias Anemia, pancytopenia A Nelson Avery, MD 45

46 Nystatin Another polyene that binds to fungal cell membrane ergosterol to produce leaky pores Used topically or orally (not absorbed from GI tract but can use to treat oral candidiasis) A Nelson Avery, MD 46

47 Azoles Agents: triazoles: fluconazole, itraconazole imidazoles: clotrimazole, ketaconazole, miconazole, etc. Block ergosterol synthesis disrupting membrane function (inhibit fungal P-450 that converts lanosterol to ergosterol, so is counter effective to use amphotericin which binds to ergosterol) Fluconazole is the only azole that effectively enters the CSF A Nelson Avery, MD 47

48 Azoles: Toxicity é LFTs, liver damage Hormonal synthesis inhibition à gynecomastia Anemia, ê WBC & platelets ê K+ Nausea & vomiting, dizziness, HA, psychological, fatigue Interactions: à ê P-450 à é levels of many drugs including oral hypoglycemics, warfarin, protease inhibitors, some antihistamines (à arrhythmias) A Nelson Avery, MD 48

49 Flucytosine Accumulates in fungi via a permease and converted by cytosine deaminase to 5-fluorouracil (5-FU), which inhibits thymidylate synthase. Used with amphotericin B in candidemia or cryptococcal meningitis Toxicity: bone marrow suppression A Nelson Avery, MD 49

50 Terbinafine Inhibits squalene epoxidase causing high levels of squalene which inhibits ergosterol synthesis. Orally active, accumulates in keratin, used for dermatophytoses Toxicity: GI irritation, skin rash, headaches, é LFTs A Nelson Avery, MD 50

51 Griseofulvin Binds to microtubules, preventing cell division (disrupts mitosis) Given orally, accumulates in skin and nails Toxicity: HA, nausea & vomiting, blurred vision, lethargy Disulfiram-type reaction with alcohol à é HR & flushing ê Effect of coumadin (ê PT) and BCPs (ê pregnancy protection) Erythema multiforme, serum sickness, urticaria;; acute porphyria A Nelson Avery, MD 51

52 Antimalarial Agents A Nelson Avery, MD 52

53 Antimalarial Drugs v Tissue schizonticide: primaquine v Blood schizonticides: quinine chloroquine mefloquine pyrimethamine Toxicities of primaquine and mefloquine are seizures and psychosis Toxicity of pyrimethamine is folic acid inhibition à bone marrow depression, hemolysis with G6PD deficiency A Nelson Avery, MD 53

54 Quinine Used to treat chloroquine-resistant strains of malaria Cinchona alkaloid Interactions: é digoxin é warfarin (displaces from albumin, inhibits its metabolism) à ê prothrombin à é PT A Nelson Avery, MD 54

55 Quinine: Toxicity Cinchonism: ê hearing (transient), tinnitus, dizziness, HA, N/V, postural ê BP;; arrhythmias and prolonged QT (quinidine-like) Fever Renal failure (reversible) Hemolytic anemia, DIC, ê platelets Blindness (recovery is slow, occurring over months) Seizures, coma Peripheral neuropathy Hypoglycemia (é insulin) A Nelson Avery, MD 55

56 Chloroquine For clinical cure and prophylaxis of all species of Plasmodium (inhibits plasmodial DNA and RNA synthesis);; treatment given with primaquine Many areas in world have resistant strains Toxicity: It is a severe poison in overdose (cardiovascular collapse, seizures, deafness, tinnitus, N/V/D) ê K+ Retinal and visual changes (can be irreversible and progress) May exacerbate psoriasis or porphyria Give cautiously with G6PD deficiency A Nelson Avery, MD 56

57 Mefloquine Other Antimalarial Agents: Other Quinolines For chloroquine-resistant and multi-drug resistant falciparum malaria (prophylaxis and treatment) Toxicity: psychiatric reactions Primaquine Active against late hepatic stages of falciparum malaria Toxicity: hemolytic anemia w/ G6PD deficiency A Nelson Avery, MD 57

58 Other Antimalarial Agents: Dihydrofolate Reductase Inhibitors Pyrimethamine plus sulfadoxine (Fansidar ) Toxicity: hemolytic anemia G6PD deficiency, bone marrow depression Atovaquone plus proquanil (Malarone ) Toxicity: nausea, vomiting, diarrhea, anorexia, abdominal pain, HA, dizziness A Nelson Avery, MD 58

59 Antiviral Agents A Nelson Avery, MD 59

60 Amantadine & Rimantadine Used for type A influenza (blocks the coating of virus particles) and Parkinson s disease (dopamine agonist and anti-cholinergic effect) Toxicity: Confusion, hallucinations, é seizure activity Anticholinergic: weakness, fatigue, nausea, dizziness, lightheadedness, urine retention, dry mouth, mydriasis and blurred vision, toxic psychosis Arrhythmias: ventricular fibrillation, torsades de pointes A Nelson Avery, MD 60

61 Oseltamivir & Zanamivir Used for type A influenza Inhibits viral neuraminidase à inhibit release of virus from epithelial cells of respiratory tract Toxicity: nausea, vomiting, bronchitis A Nelson Avery, MD 61

62 Ribavirin Used for inhalation therapy in respiratory syncytial virus (RSV) and in combination therapy with interferon for chronic HCV Toxicity: respiratory depression, ê BP, hemolytic anemia, é bilirubin A Nelson Avery, MD 62

63 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for HIV [several end in vudine ] Toxicity of group: ulcers in mouth, pancreatitis, lactic acidosis, severe hepatomegaly with steatosis Lamivudine: hepatomegaly, lactic acidosis Zidovudine (AZT): bone marrow suppression, hepatomegaly, HA, rash, fever, paresthesias, myopathy, lactic acidosis A Nelson Avery, MD 63

64 NRTIs (cont.) Stavudine: neuropathy, hepatomegaly, lactic acidosis Didanosine: painful sensory neuropathy, pancreatitis, hepatomegaly, blindness (optic atrophy) Zalcitabine: neuropathy, rash, pancreatitis Abacavir: severe hypersensitivity reactions A Nelson Avery, MD 64

65 Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Toxicity of group: arrhythmias, rash, hepatotoxicity Delavirdine: skin rash, teratogenicity, lifethreatening arrhythmias Nevirapine: severe hypersensitivity, skin reactions, hepatotoxicity Efavirenz: neurotoxicity, é lipids, teratogenicity A Nelson Avery, MD 65

66 Protease Inhibitors for HIV [end in navir ] Toxicity of group: hyperglycemia (new onset DM);; fat redistribution, hyper-bilirubinemia, rhabdomyolysis, nephrolithiasis, arrhythmias Amprenavir and Fosamprenavir: hypersensitivity: rash, Stevens-Johnson Atazanavir: hyperbilirubinemia Indinavir: hematotoxicity & nephrotoxicity Nelfinavir: diarrhea and hypersensitivity Ritonavir: nausea & diarrhea, inhibition of drug metabolism (used to raise co-administered drug levels) Saquinavir: neutropenia Tipranavir: é LFTs and lipids A Nelson Avery, MD 66

67 Other HIV Drugs Tenofovir Nucleotidereverse transcriptase inhibitor Enfuvirtide Fusion inhibitor A Nelson Avery, MD 67

68 Antiviral Agents for CMV Cidofovir: on bioactivation inhibits DNA polymerases;; nephrotoxic Fomivirsen: antisense nucleotide that binds to mrna inhibiting early protein synthesis Foscarnet: inhibits viral RNA and DNA polymerases;; nephrotoxic, GU ulceration, HA, seizures in high dose Ganciclovir: inhibits DNA polymerase;; hematotoxicity, neurotoxicity Vidarabine: antimetabolite;; severe neurotoxicity and hepatic toxicity A Nelson Avery, MD 68

69 Antiviral Agents for HSV Acyclovir: phosphorylated by viral thymidine kinases à metabolite substrate and inhibitor of DNA polymerase, causes DNA chain termination Toxicity: GI distress and HA;; IV infusion à crystalluria, delirium, tremor, seizures Famciclovir Valacyclovir A Nelson Avery, MD 69

70 Study Questions 1. What is the neurological complication to using carbapenems (like imipenem) after a week? [seizures] 2. Name an antibiotics that causes a red man syndrome. [vancomycin, rifampin] 3. Which antibiotic is associated with gray syndrome in neonates? [chloramphenicol] 4. Two effects of chloramphenicol on blood production? [aplastic/ idiosyncratic vs. allergic marrow] 5. Which antibiotic is associated with yellow-brown staining of teeth in children? [tetracycline] 6. What orthopedic problem can occur with using fluoroquinolones? [tendonitis and ruptured tendons] A Nelson Avery, MD 70

71 Study Questions 7. What happens if you mix metronidazole (Flagyl ) with alcohol? [disulfiram-like reaction] 8. What are 2 serious side effects from nucleoside analogs for HIV? [pancreatitis, lactic acidosis, marrow toxicity, hepatomegaly with steatosis] 9. Name 2 serious side effects from protease inhibitors. [é glucose, lipodystrophy, hepatotoxicity, kidney stones] 10. List the triad of conditions found with INH overdose. [repetitive seizures, metabolic acidosis, coma] 11. What is the antidote for INH poisoning? [vit. B6, pyridoxine] 12. What does rifampin do to secretions, including urine and tears? [red orange color] A Nelson Avery, MD 71