2.3 policastro antimicrobials...sideeﬀectsof$ anretroviral medicaons- side effect drugs lactic...

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

2.3 policastro antimicrobials...sideeﬀectsof$ anretroviral medicaons- side effect drugs lactic...

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