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TRANSCRIPT
An#microbials
Michael Policastro, MD Director, Medical Toxicology, QESI
Clinical Assistant Professor, WSU
Overview
• An#microbials • An#mycobacterials
• An#virals • Disinfectants • An#fungals • An#parasi#cs • Adverse Effects by Systems
An#bio#cs
• Cell Wall (β-‐ lactams, Glycopep#des-‐ Vanc)
• Cell membrane (Polymyxin B) • Protein synthesis (Aminoglycosides,Tetracycline, Linezolid
Macrolides, Chloramphenical)
• Nucleic Acids (Fluoroquinolones, Metronidazole, Rifampin) • An7-‐metabolites (Sulfonamides,Trimethoprim)
Β-‐lactam
• Penicillins: -‐ Anaphylaxsis, SZ ( Picrotoxin binding site GABA), ↑K
– Hoigne Syndrome: males, fear/illusion, apprehension
– Jarisch-‐Herxheimer: fever, chills, rash; lysed bacteria
• Cephalosporins: nMTT side chain • ( moxalactam, cefazolin, cefoperazone, cefmetazole, cefmandole, cefotetan)
• hypothrombinemia, Vit. K epoxide reductase inhibi7on, • disulfiram rxn
• Cefaclor = serum sickness • Imipenem: Seizures, Picrotoxin binding site
• No PNC cross reac#vity with Impenem, Aztreonam
Disulfiram reac#ons
• Metronidazole • Cephalosporins with NMTT side
chain: -‐ cefoperazone, cefamandole,
moxalactam, cefotetan, cefmetazole
• Chloramphenical • Nitrofurantoin • Trimethoprim-‐sulfamethoxazole • Griseofulvin • OSHA: chlorpropamide,
tolbutamide • Mushrooms:
Coprinus,Clitocybe,Tricholoma
Clinical Environmental Health and Toxic Exposures .Sullivan and Kreiger.2001 . Table 18-‐4. P.238
Vancomycin
• Inhibits cell wall synthesis binding D-‐alanyl-‐D-‐alanine cell wall precursors
• Tox: Red Man syndrome, ototoxicity, nephrotoxicity
Aminoglycosides
• Inhibits 30s ribosomal subunit
• Nephrotoxicity, Ototoxicity, Ve#bulotoxicity • NMB: inhibit presynap7c release of ACH
Chloramphenical
• Inhibits 50s ribosomal subunit
• Metabolism: glucuronyl transferase • limited conjugate in children • “Grey baby”-‐vomi#ng,anorexia, ash color, met acidosis
• Aplas#c anemia, peripheral neuropathy , op#c neuri#s , metabolic acidosis, cardiovascular collapse
Drugs that undergo primary Synthe#c Phase II Biotransforma#on that you may forget
• Glucuronida#on : Valproic acid, lamotrigine, opioids, APAP, irinotecan, 5-‐FU, chloramphenical
• Acetyla#on: INH, hydrazines, Sulfonamide, Dapsone, amonafidine
Macrolides/Ketolides/Licosamides
• Inhibit 50s ribosomal subunit • Eythromycin,azithromycin,clarithromycin, Clindamycin • Inhibit 3A4 except azithromycin, ↑QT • Inhibit PGP intes7nal = Digoxin • Chronic cholesta7c hepa77s, sensory neural hearing
loss • Telithromycin: carbamate side chain; cholinergic crisis in
Myasthenia pts • Clindamycin: C.diff, Stevens-‐Johnson, NMB,
dysrhythmias
Tetracycline
• Inhibits 30s/50s ribosomal subunit
• Teratogen-‐ Teeth discolora#on, hypoplas#c enamel, seen amer 4th month
• Benign intracranial hypertension • Phototoxicity, pneumoni#s, drug-‐induced Lupus • Minocycline: Lupus like syndrome, Diabetes Insipidus ( DI)
• Democycline: nephrogenic DI
Linezolid
• Inhibits N-‐formylmethionyl-‐ tRNA • HA, thrombocytopenia
• Brown discolora#on tongue • Weak MAO inhibitor
• Serotonin syndrome with SSRIs
Nitrofurantoin
• Pulmonary: dyspnea/cough, inters##al fibrosis
• Rash, Lupus like syndrome • Neuropathy peripheral • Disulfiram reac#ons
Fluoroquinolones
• Inhibit DNA gyrase/topoisomerase • Binds Ca#ons, esp. Mg2+
• Seizures: Binds Mg2+, + NMDA, (-‐) GABA
• QTc= sequestra#on Mg2+
• Car7lage/Tendon damage
• Hepatoxicty • Psychosis, serum sickness
Metronidazole
• Metallic taste • Peripheral neuropathy • Disulfiram reac#on
Sulfonamides
• Inhibit para-‐amino acid/para-‐amino acid glutamic acid
• Folate synthesis inhibitor • Hypersensi#vity Rxns • MetHgb, hemolysis • Pneumoni#s, hepatotoxicity-‐ cholestasis, asep#c menigi#s
Folate Inhibitors-‐ An7metabolites
• MTX
• Proguanil • Pyrimethane • Dapsone • Atovaquone • Sulfonamides • Trimethoprim
• Triamterene
• Sulfasalazine • Aminopterin • 5-‐FU
An#mycobacterials-‐ TB Drugs
• INH • Rifampin
• Ethambutol
• Pyrazinamide – nico#namide analog, hepa##s, gout
• Cycloserine • Para-‐Aminosalicylic acid-‐ hepa##s, hypersensi#vity reac#on, thrombocytopenia
• Capreomycin
INH
• OD: Seizures, coma, metabolic acidosis
• INH Tox : op#c neuri#s, pancrea##s, hepa##s • TOX: +/-‐slow acetylators, 2E1 • TX: Pyridoxone
Goldfrank’s Toxicologic Emergencies. 6th edi#on. 2006. Figure 55-‐3 p.863
B6 ( Pyridoxine)
• Tx: hydrazines, ethylene glycol • Dose: INH-‐ gram/gram
• OD: sensory neuronal neuropathy, ataxia
Hydrazines
• INH • Non-‐selec#ve MAO A/B Inhibitors: -‐Phenelzine, Isocarboxazid, Procarbazine
• Hydrazine ( Diamine) • Monomethyhydrazine • Gyromitra • Ginkgo Biloba seeds ( 4-‐Methoxypyridoxine)
Rifampin
• Binds B units DNA dependent RNA polymerase
• * 3A4 inducer • Red/orange body fluids • False nega#ve PPD • TOX: hepa##s, Lupus like syndrome, ARF, thrombocytopenia, hemoly#c anemia, eosinophilic coli#s
Ethambutol
• 1st line in pregnancy • Chelates metal
• ** Zn chela#on = op#c neuri#s • ** shim wavelength discrimina#on
• ** loss red/green discrimina7on
Cycloserine
• Analog of alanine • Neuro dysfunc7on • Sz, psychosis • Contraindicated in Seizure Pa7ents • Safe in breast feeding
Capreomycin
• * Hearing loss, 7nnitus • Preo#nuria, electrolyte loss • Sterile abscess at injec#on sites
An#malarial
• Quinine • Chloroquine/Hydroxychloroquine/Amodiaquine • Primaquine-‐ MetHgb, Contraindicated Pregnancy • Mefloquine: Neuropysch-‐ Sz, psychosis
• Proguanil/Pyimethamine/Suldoxine • Atovaquone • Dapsone • Artemisinin: very safe, sz
Chloroquine • Cardiac: Class Ia effect, neg
ionotropy, VT, VF
• Hypokalemia • Sz, transient blindness • TX: AC, Hypokalemia
protec#ve Do NOT treat aggressive, diazepam
Quinine • Cinchoa tree ( Rubiacea)
• Cinchoism: auditory, GI, swea7ng, HA, vasodila7on
• Cardiac: Class Ia affect, myocardial depression, phase 0 depression, vasodila#on
• Heme: thrombocytopenia, pupura, hemolysis
• CNS: Blindness, Tinnitus/deafness
• Hypoglycemia-‐ sulfonyurea like
• TX: MDAC, Bicarb, ?Octreo7de
An#malarials:Folate Inhibitors
• Atovaquone: Rash, erythema mul#formae
• Proguanil: GI, megaloblas#c anemia, rash
• Pyrimethamine: N/V, SZ, megaloblas#c anemia
• Dapsone
Dapsone
• Bacteriosta#c synthe#c sulfone, inhibits folic acid synthesis, binds dihydropterate synthase
• Oxidizer, MetHgb, Hemolysis, also Sultemoglobin • “Sulfone Syndrome” delayed hypersensi7vity syndrome =
fever, eosinophilic pneumonia, derma##s, hepa#c necrosis
• Also: thrombocytopenia, neutropenia, neuropathy • TX: MDAC, Methylene Blue, Exchange transfusion
HIV Drugs
Nucleoside Reverse Transcriptase Inhibitors (NRTI) zidovudine/Retrovir (AZT, ZDV) didanosine/Videx, Videx EC (ddI)
zalcitabine/HIVID (ddC) stavudine/Zerit (d4T) lamivudine/Epivir (3TC) abacavir/Ziagen (ABC)
Non-‐Nucleoside Reverse Transcriptase Inhibitors
(Non-‐ NRTI ) nevirapine/Viramune delavirdine/Rescriptor efavirenz/Sus=va
Nucleo7de Analogue tenofovir DF/Viread (TDF)
Adefovir/Hepsera Emtricitabine/Emtriva
Protease Inhibitors (PI) indinavir/Crixivan ritonavir/Norvir
saquinavir/Invirase,Fortovase nelfinavir/Viracept
amprenavir/Agenerase lopinavir/ritonavir, Kaletra
Atazanavir/Reyataz
Enfuvir#de/ Fuzeon
Fusion (entry) inhibitors
HIV Drug Toxici#es
NRTI -‐lac7c acidosis, impaired β –oxida#on TX: L-‐carni7ne -‐peripheral neuropathy -‐Lipodystrophy syndrome
NNRTI -‐ Skin rashes ( Stevens-‐ Johnson,
TEN, Eosinophilic systemic) * nevirapine -‐ Hepatotoxicity, pancrea##s -‐ * Efavirenz-‐ neurotox
• Protease Inhibitors -‐Dyslipidemias, Hyperglycemia *ritanovir-‐ hepatotoxicity, PGP
inhibitor *Indinavir-‐nephrolithiasis
Side effects of an7retroviral medica7ons
Side Effect Drugs
Lactic acidosis Nucleoside reverse transcriptase inhibitors, especially didanosine, stavudine
Hypersensitivity reaction Abacavir, nevirapine
Liver toxicity Saquinavir, ritonavir, nelfinavir, tenofovir, nevirapine, efavirenz, atazanavir
Pancreatitis Didanosine, stavudine, zalcitabine, lopinavir/ritonavir
Nephrolithiasis Indinavir
Acute tubular necrosis Tenofovir
Acute interstitial nephritis
Indinavir, ritonavir
Myelosuppression Zidovudine
Myopathy Zidovudine
Neuropathy Stavudine, didanosine, zalcitabine
An#Virals
• Fusion Inhibitors-‐ Guanosine Analogs
-‐Acyclovir -‐Famciclovir
-‐Ganciclovir -‐Valacyclovir
-‐Valganciclovir • Pyrofosfate Analog -‐ Foscarnet
• M2 protein Blockers
-‐ Amantadine, Rimantadine • Neurominidase Inhibtors
-‐Oseltamivir • Other -‐ Ribavirin
-‐ Cidofovir -‐ Palivizumab
An#virals
• Amantadine: pre-‐synap7c DA blockade; TOX: Hyperthermia,↑QT, ? An#cholinergic
• Oseltamivir: GI • Acyclovir: Neurotox/Nephrotox-‐ crystal forma7on • Ganciclovir: Re7nal tox • Valacyclovir: TTP • Foscarnet: *chelates divalet metals: Ca, Mg, Fe, Zn,
Nephrotox • Cidofovir: Nephrotox, OD TX: * Probenicid decreases renal
clearance/renal failure • Ribavirin: teratogen,sperm morphology
An#sep#cs, Disinfectants, Sterilants
• An7sep7c: Agent applied to living #ssue to kill/inhibit microorganism
• Disinfectant: Agent applied to inanimate objects to kill microorganisms.
• Sterilant : Agent applied to inanimate objects to kill all microorganisms and spores
Disinfectants
• Formalin: 37 % Formaldehyde + 15 % methanol, Formaldehyde IARC 1 classifica7on
• Phenol ( carbolic acid ) : severe burns skin /oral white ulcers, sz, met acidosis, rabbit syndrome (↓DA)
-‐TX: PEG ,Isoproponal – skin burns
• Benzalkonium chloride: quarternary ammonium-‐ occasional paralysis, NMJ-‐ ACHE inhibi#on, occ. asthma
An#sep#cs • Chlorhexidine: vaporized converts p-‐chloraniline, MetHgb
• Hydrogen peroxide: Conc. dependent, possible air emboli, local injury
• Iodophors: (I2 ) elemental iodine, (I-‐ ) iodide: inges#on, blue-‐ purple emesis with starch, false posi#ve Hematest (orthotoluidine), caus#c, GI bleed psuedohyperchloremia.
TX: Covert Iodine to Iodide with milk/starches, thiosulfate
• Potassium Permanganate: oxidizer, reacts with H20 to form manganese dioxide ( stains areas brown-‐black), potassium hydroxide and molecular oxygen.
-‐Acute : local injury, MetHGB. -‐ Chronic: possible Manganese poisoning-‐ ams, parkinsonism, behavior d/o. -‐TX: Skin stains-‐ dilute oxalic acids, NAC
Sterilants
• Ethylene Oxide: spontaneous abor7ons,Oligiospermia
mutagenic, Possible carcinogenic-‐ leukemia, gastric CA, motor/sensory neuropathies
• Glutaraldehyde: vapor-‐ cp, palpita#ons, mucosal irritant
An#fungals
• Amphotericin -‐Liposome B complex to reduce
nephrotox -‐Nephrotox -‐Fever, chills due to PGE2 disrup7on -‐↓ K, Mg, WBC, Plts -‐ Tinnitus
• Triazole (fluconazole, itraconazole,
terconazole, voriconazole) -‐Inhibits ergosterol synthesis, ↑LFTs -‐ Inhibits * 3A4
• Imidazoles ( ketaconazole, clotrimazole, econazole,
miconazole) -‐Inhibit fungal cell walls • 3A4 Inhibitors, ↑QT with
terfenadine,cisapride,astemizole • Ketoconazole: Alopecia,
gynecomas7a, adrenal suppression, androgen suppression, hepa77s
An#helmin#cs
• Mebenazole: teratogenic,rash
• Thiabendazole: GI, cholestasis,leukopenia,Hypersensi#vity rxn • Levamisole: ↓Plts, encephalopathy, TEN
• Niridazole: Sz • Piperazine: Angioedema, sz
• Metrofonate: inhibits ACHE, cholinergic crisis
• Hyocanthone:mutagenic, carcinogenic • Ivermec#n: Facial edema, bullous skin
• Suramin: Renal/adrenal insufficency, TEN • An7mony ( 3+/5+): GI, derma77s; TX:BAL
Neurologic Adverse effects
• AMS: Ethambutol, PNC, Chloramphenical, Mefloquine, Efavirenz • Intracranial Hypertension: Tetracyclines, Albendazole • Seizures: PNC, Cephalosporins, Rifampin, Sulfonamides, Fluoroquinolones,
INH, Ethylene oxide, Imipenim • Neuromuscular blockade: Polymyxin B, Fluoroquinolones,colis#methate
Aminoglycosides, Clindamycin, Vancomycin, Benzalkonium chloride • Myosi7s: Chloroquine, PNC, Rifampin, Sulfonamides, Zidovudine • Peripheral Neuropathy: Chloramphenical, Flagyl, Ritanovir, Didanosine,
Zalcitabine,Stavuidine, amprenavir • Movement Disorder: Potassium Permanganate, Phenol • Ototoxicity: Vancomycin, Chloroquine/Quinine, Aminoglycosides,
erythromycin • Op7c neuri7s: Ethambutol, Chloramphenical, Cidofovir, Gancyclovir • Re7nal Blindness: Quinine, Hydroxychloroquine
Skin Rash Adverse Effects
• “Red Man”-‐ Vancomycin • “Grey baby”-‐ Chloramphenical • Blue ( MetHgb): Sulfonamides,Dapsone, Primaquine,
chloroquine, nitrofurans, • Stevens-‐Johnson: PNC, Cephalosporins, Sulfa, nevirapine • TEN: PNC, Sulfas, nevirapine • Vesiculobullous: PNC, Rifampin, Sulfonamides, Griseofulvin • Vasculi7s: Levamisole • Acute Hypersensi7vity Syndrome: Sulfas, Bacitracin,
Clindamycin, Lincomycin, Nitrofurazone, nevirapine • Alopecia: Selenium Sulfide
Renal/GU Adverse Effects
• Acute Tubular Necrosis: Aminoglycosides, Acyclovir, Amphotericin,Pentamidine, Polymyxins, Fluroquinolones,Foscarnet, Ritonavir, Tenovir, Phenazopyridine
• Acute Inters77al Nephri7s: PNC,Ampicillin,Rifampin,Sulfonamides, Vancomycin
• Nephrolithiasis/Obstruc7on: Indanavir, Sulfonamides ( crystal deposits), Acyclovir
• Tubular dysfunc7on: Aminoglycosides, Amphotericin, Tetracycline, Griseofulvin
• Decrease Sperm: Ethylene oxide , Nitrofurantoin, Ribavirin
• Abor7ons: Ethylene Oxide
Electrolyte Adverse Effects
• Diabetes Insipidus: Amphotericin, Foscarnet, Minocycline, Rifampin, Streptozotocin
• Hypokalemia ( ↑ QT): Aminoglycosides, Amphotericin, Chloroquine
• Hyperkalemia: PNC, Triamterene, Trimethoprim
• Hypocalcemia (↑QT): Aminoglycosides, Neomycin • Hypomagnesium ( ↑QT): Aminoglycosides, Foscarnet,
Fluroquinolones
Teratogens
• Fluconazole: Abnormal facies, cardiac, femoral bowing
• Quinine: Hypoplasia 8th CN • Streptomycin: Hearing loss
• Tetracycline: Teeth discolora#on, hypoplas#c enamel, seen amer 4th month
• Trimethoprim: NTD, hypospadias
• *See Folate inhibitor list*
Hematologic/Immune
• Type I: IgE: PNC, tetracyclines, Sulfonamides, Nitrofurantoin,Streptomycin
• Type II: An#body IgG/IgM-‐ cytopenias: Amoxicillin, Sulfonamide
• Type III: Immune Complex IgG/IGM-‐ Serum Sickness: Cefaclor
• Type IV: T-‐ lympocyte-‐ contact derma##s: Topical PNC • Oxida7ve Hemolysis/MetHgb: Dapsone, Nitrofurantoin, Phenol,
Sulfonamides, Novobiocin
• Agranulocytosis: B-‐lactams, Cephalosporins, Chloramphenical, Dapsone, Ganicyclovir, Rifampicin, Sulfonamides, Vancomycin
• Thrombocytopenia: Amphotericin, Indinavir, Levamisole, Quinine, Rifampin, Trimethoprim-‐sulfamethoxazole, Vancomycin
• TTP: Valacyclovir