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8/6/2019 Antibiotic Pharm
1/28
7/31/20
Pharm
,
Matthew Greer
Fe Absorbed in duodenum / proximal jejunum
Deficient patient can absorb ~230mg/day
n y o sor e n errous orm
Vitamin C converts ferric to ferrous
PO4 and Ca reduce converting ability
Heme Fe is best absorbed (eat red meat)
Spleen recovers Fe from extravascular hemolysis
Oral drugs better then parenteral
Gulconate < sulfate < fumarate Order of concentration and side effects
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Fe
Parenteral Fe = Iron dextran Only for extensive chronic blood loss or if oral meds can not
Can cause anaphylaxis, bronchospasm
Monitor therapy by reticulocyte count
Improve in 1-2 weeks (Hb levels take months)
Overdose = abd pain, cyanosis, diarrhea / vomitting
Treat with deferoxamine if> 3.5 m /L
Excreted from kidney as feroxamine
Contraindicated in renal failure Chronic overload use deferasirox
Folate If deficient will see macrocytic anemia
Give leucovorin (bypass DHFR step)
ormo ast c ce s seen n rs
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Anti-microbial basics
Inhibitor vs bactericidal MIC = concentration which inhibits growth
= owest concentrat on w c s .
Killing potential
Bactericidal = can kill bacteria (during division)
Fast action, not dependent on immune system
Bacteriostatic = inhibit growth (prevent division)
Slow action, require immune system
Anti-microbial basics Specturm
Narrow = single species
son az myco ac er a
Extended = gram-pos and neg
Ampicillin
Broad = destroys many species
Can cause superinfections
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Anti-microbial Properties
CDK = greater bactericidal activity with conc Can be given fewer times a day at higher conc to kill more of
TDK = conc does not affect killing rate
Drug must stay above MIC levels
PAE = suppression of growth remains after drug falls
below the MIC
Dru s with PAE and CDK = once a da dosin
Aminoglycosides and FQs
Anti-microbial Basics Allery = penicillins, cephalosporins, sulfas
Age = tetracyclins cause bone/teeth damage
Not for children or pregnant women
Pregnancy
Do not give: Tetracycline, Aminoglycosides, Macrolides (-
mycins), FQs, or sulfas
Basically penacillins and cephalosporins are cool
Man antibiotics reduce efficac of HBCPs
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Prophylactic treatments
Rheumatic heart disease = pen G
Bac endocarditis = amox- / ampicillin
Vert HIV transmission = Zidovudine
Influenza type A = Amantadine or Rimantadine
TB = Isoniazid (INH)
Most Important Combination -lactam with aminoglycoside
Synergistic effect, both are bactericidal and -lactam uptake
All combinations are bactericidal with bactericidal
Do not have to both be CDK though
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Superinfections
After therapy normal flora is wiped out and C. difficle orcandida can take over
rugs a are roa specturm :
Tetracyclins
Chloramphenicol
Ampicillin
Cephalosporins
Clindam cin
-lactams Penicillins, cephalosporins, carbapenems, and monobactam
All have -lactam ring
Required for action / target for resistance
Analogs of D-ala-D-ala = Inhibit transpeptidase
No transpeptidase = cell wall breakdown / death
Bactericidal with TDK
Knock out enzyme, not direct action
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-lactam Resistance
-lactamase = enzyme which hydrolyzes ring Produced by staph (and many others)
ram-neg ave toug to reac ce wa
MRSA = PBP is altered so no -lactams work
Penicillins Renal excretion, high therapeutic index, safe for preg
Standards Pen G, Phenoxymethyl pen (V)
Renal excretion by probenecid
Used for syphilis, meningococcal infections, tetanus,perfringins,
actinomycosis
Antisaph Methicillin,Nafcillin, Dicloxacillin
Inherint -lactamase resistance
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Penicillins
Amino Ampicillin, Amoxicillin Often combined with lactamase inhibitors
mp = ster a monoctogenes
Broad specturm = superinfection
Amo = completely absorbed ( risk of PMC)
Anti-pseudomonal Carbenicllin, Ticarcillin, Pipercillin,
Mezlocillin
Combined with lactamase inhibitors
Pipercillin is DOC for anti-pseudomonas
-lactamase Inhibitors Clavulinic acid = ~60% oral BA
Combined with amoxicillin and ticrcillin
u actam com ne w t amp c n
Tazobactam w/ pipercillin
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Cephalosporins
More resistant to lactamase inhibitors still have -lactam ring though
o not cover
Listeria, Atypicals, MRSA, Enterococci
Each generation has better gram-neg effect
1st Generation Cephalosporins Cefazolin (parenteral) and cephalexin (oral)
Great for gram-pos, weak gram-neg
Gram-neg use = PEK
Proteus
E. coli
Klebsiella
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2nd Generation Cephalosporins
Parenteral = Cefuroxime, Cefoxitin, Cefotetan
Oral = Cefaclor
Gram-neg use: Pek +
H. influenzae
N. meningitidis Note: cefotetan and cefoxitin can handle Bacteroides fragilis (anaerobic)
3rd Generation Cephalosporins Parenteral = Cefotaxime, Ceftriaxone, Ceftazidime,
Cefoperazone
ra = e x me
Lactamase resistant
Uses = PEK-HN +
Pseudomonas
Enterbacteriacea
Neisseria = good, Listeria = Ampicillin
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Ceftriaxone (3rd gen)
Gonorrhea = single dose
Bacterial meningitis = great if not listeria
Typhoid Fever
Acute otitis media = broad spectrum
4th Generation Cephalosporin Parenteral only = Cefepime
Just like 3rd generation but better lactamase resistance
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Carbapenems
Imipenem = gram-(+), gram-(-), and anaerobes Only in ICU Severe enterobacter infections
y ro yze y e y ropept ase- se zures
Block with cilastatin
Meropenem = not degraded by DHP-1
Monobactam Azetreonam
Used for H. influenza and pseudomonas
o ac v y on gram-pos or anaero es
Can be used on penicillin sensative patients with pseudomonal
infection
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Non--lactam Cell Wall Inhibitors
Vancomycin = binds D-ala-D-ala to block glycosylation(before cross-linking)
n y or gram-pos ves
Enterococci, MRSA, C. difficle
Resistance by cell wall (intermediate) or change D-ala-D-ala
D-ala-D-lactate
Adverse Effect = RED MAN (flushing)
Nephrotoxic and ototoxic as well
Non--lactam Cell Wall Inhibitors Fosfomycin = prevents NAG NAM formation
First step of PG synthesis (inhibits transferase)
ot gram- an gram- - a ecte
Bacitracin = Inhibits recycling of C55
Nephrotoxic so only topical
Great for gram-(+)
Cycloserine = analog of D-ala
Secondary therapy for TB
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Nucleic acid synthesis inhibitors
Fluoroquinolones (-floxacin) = inhibit DNA gyrase Expanded gram-(-) with mycoplasma and chlamydia
=
Folate synthesis inhibitor
Cotrimoxazole = Sulfamethoxazole and trimethoprim
Used for P. jirovecipneumonia in AIDS = syn bactericidal
Metronidazole = binds DNA and proteins
First reduced to cytotoxic intermediate
or . i superin ections
Preg category X and disulfram like reaciton
Methenamine = becomes formaldehyde in acidic urine
Conversion in tissue in presence of sulfas (BAD)
FQs (-floxacins) Fluorinated analogs of nalidixic acid
Have CDK and PAE
DOC for anthrax
Typhoid fever (w/ penicillin allergy)
Gastroenteritis
Respiratory FQs (levofloxacin, gemifloxacin, moxifloxacin)
Better Gram-(+) effect
Levo is DOC for CAP
MAC
Adverse
Seizures (when combined with NSAIDs)
Cartilage damage, QT prolongation
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Sulfonamides
Analog of PABA = blocks dihydropterate synthesis
Bacteriostatic normally
Bactericidal in urine and w/ combination (pyrimethamine)
Adverse
Metabolic product crystalluria in acidic urine (so fluid)
Can cross placenta, bind to albumin kernicterus
Hemolysis in G6PD
Uses
Silver sulfadizaine = topically for burns
Sulfasalazine (sulfapyridine w/ 5-ASA) = UC and RA
Protein Synthesis Inhibitor Aminoglycosides (Bactericidal)
Binds 30S subunit, at high doses toxic peptides (pores) Metabolic inactivation
n y ero c organ sms transport requ res
Adverse = otoxicity, nephrotoxicity, no oral
Tetracycline (Bacteriostatic) Binds 30S subunit, blocks t-RNA from A site
Efflux pump, ribosome protection protein
Adverse = superinfections, bone / teeth, vestibulo-toxicity
Absorption impaired by dairy
acro es ac er os a c Binds 50S subunit preventing translocation
50S methylation = affinity
Adverse = binds motilin, inhibits Cyt-P450, transiet ototoxicity
Mostly alternative for pen allergy
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Aminoglycosides (parenteral only)
Streptomycin Least nephrogenic
ses: , p ague, tu arem a
Gentamicin
Broad specturm (kelbsiella, proteus, Ps. aeurginosa)
Serious gram-(-) infections, combined with -lactams
Amikacin
-
Tobramycin
Superior against pseudomona (w/ pipercillin = synergistic)
Tetracyclines Doxycycline
Post exposure prophylaxis for plague and tularemia
or many s c amy a, r c etts ae, cox e a,
Lyme disease
Tigecycline
Derivative from minocycline
Active against vanco resistant MRSA
No activity against proteus or pseudomonas
Demeclocycline
Causes DI (used to counter SIADH)
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Macrolides
Erythromycin DOC C. diptheriae, B. pertussis, M. pneumonia
Chlamydial infection in infants (tetrcyclines contraindicated)
Not active against MAC
Inhibits Cyt-P450
Azithromycin
Use:MAC, toxoplasma, H. influenzae, chlamydia, legionella
No effect on Cyt-P450
Clarithromycin Similar activity as azithromycin but inhibits Cyt-P450
Clindamycin Same binding site as macrolides
DOC for bacteroides fragilis (anaerobics)
Broad spectrum = leads to superinfection
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Protein Synthesis Inhibitors
Linezolid Binds 50S subunit to prevent ribosome assembly
Used for vanco resistant bugs
Adverse: Inhibits MAO, peripheral and optic neuropathy,myelosuppresion
Quinupristin / dalfopristin Quin binds macrolide site (methylase = resistant)
Dalf inhances quin binding (metabolic inactivation)
Used for vanco resistant bugs
Blocks Cyt-P450
oramp en ca Blocks peptidyl transferase (stops elongation)
Similar site as macrolides Alternate drug only (due to resistances and myelosuppression)
Gray-baby syndrome and blocks Cyt-P450
Anti-TB 1st line drugs (all are hepatotoxic)
Isoniazid (INH) Blocks mycolic acid synthesis (InhA and KasA)
Converted to active form in bacteria (KagG catalase)
Peripheral neuropathy (give B6)
Rifampin Transcription inhibitor
Binds -subunit of DNA-dep-RNA polymerase
Cyt-P450 inducer, red / orange secretions
Pyrazinamide Converted to pyrazinoic acid ( pH)
Hyperuricemia (gout)
Ethambutol inhibits arabino alactan s nthesis cell wall
Only bacteriostatic of 1st lines
Optic neuritis (red/green)
(Streptomycin)
Nephrotoxic and ototoxic
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Anti-TB
Second line Ethanionamide = INH analog
er p aera neuropa y an epa o ox c y
Capreomycin = protein synthesis inhibitor
Psychosis, seizures, peripheral neuropathy
Cycloserine = D-alanine analog (cell wall synthesis)
FQs, PABA analogs and Rifamycins are also used
MDR-TB = resistant to INH and rifampin
Leprosy Dapsone inhibits folate synthesis
Bacteriostatic
emo ys s n , per p era neuropat y, opt c neuropat y
Rifampin binds -subunit of RNA polymerase
Bactericidal for M. leprae
Clofazimine bacteriostatic
Active against MAC as well
-
Treatments
Multibacillary = all 3 for 2 years
Pausibacillary = Dapsone + Rifampin for 1 year
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Antivirals
Most are purine or pyrimadine analogs
HSV (and VZV)
Valacyclovir (DOC HSV encephalitis), Famciclovir/penciclovir
Guanine analogs
Activated by viral thymidine kinase (only in infected cells)
Virus mutates this to have resistance
Nephrotoxicity and neurotoxicity
Tirfluridine (thymidine analog)
ct vate n a ce s even non- n ecte
Topical only (for ocular keratoconjunctivitis)
Antivirals CMV
Valganciclovir
Guanine nucleoside analo
Activated by viral thymidine kinase (only infected cells
Can cause myelosuppression
Cidoforvir
Cytosine analog
Nephrotoxicity (give with probenecid to tubular secretion)
Foscarnet
norganic p osp ate ana og in i its poymerase Alternate for resistant strains only (and works against HIV)
Nephrotoxicity, neurotoxicity, hypocalcemia (chelates Ca)
Fomiversen (only for resistant strains)
Antisense gene therapy (CMV mRNA)
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Antivirals (Influenza)
Amantadine (crosses BBB) and Rimantadine Type A influenza only
n ts v ra uncoat ng y oc ng on c anne
Oseltamivir and Zanamirvir
Active against type A and type B
Neuraminidase inhibitors (prevents release of new virions)
Zanamivir is intra-nasal and can cause bronchospasm
Antivirals (Respiratory Sysctial Virus) Ribavirin
Guanine analog (inhibits RNA polymerase)
or , ronc o t s, an pneumon a pe s
Given with IFN- for HCV
Inhalational route so can cause transient wheezing
Teratogenic
Palivizumab
MAB against A antigen site of F-glycoprotein on surface of RSV
Prevents RSV infection in high risk children
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Antivirals (Hepatic)
IFNs Induce bodies natural anti-viral enzymes
eurotox c, car otox c, an cause mye osuppress on
Lamivudine = cytosine analog
Adefovir = AMP analog
Given for lamivudine resistant HBV
Enecavir = guanosine analog
Ribavirin = guanine analog
Combined with IFN- for HCV
Anti-HIV drugs Reverse transcriptase inhibitors (RTIs)
Activated by phosphorylation with cellular kinases Competative inhibit reverse transcriptase
ause m toc on r a tox c ty
Include: Thymidine analogs = Zidovudine (AZT) and Stavudine
Cytosine analogs = Lamivudine and Emtricitabine
Guanosine analog = abacavir, didanosine = dAdenosine analog
Tenofovir = AMP analog (nucleotide)
NNRTIs-
Active only against HIV-1 (enzyme specific)
Metabolized by Cyt-P450
Rashes are major side effect (CNS for efavirenz)
Nevirapine, Efavirenze, Delavirdine
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Anti-HIV drugs
Protease Inhibitors (-navirs) Affect post-translational processing = production of immature
HIV viral articles
Massive inhibitors for Cyt-P450 (Ritonavir)
Adverse effects
All have lipodystrophy besides atazanavir
Ritonvir = circumoral paresthesia
Idinavir = nephrolithiasis, indirect hyperbilirubinemia
Integrase inhibitor (Zitevir)
Prevents infection of new cells
Fusion inhibitors Enfuvirtide binds gp41 (the harpoon)
Given sub-cutaneous
Cocaine Blocks mono-amine reuptake transporter
CNS stimulant
Also HR and BP and vasoconstriction (sniffed)
Arrhythmias and respiratory depression are problematic
Becomes benzoylecgonine (test urine)
Will see crash withdrawal due to intermittant usage
Bradycardia and dysphoria
=
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Cocaine
Overdose = Cardiac abnormalities, BP, seizures Treatment = -blockers
car ac sc em a as occurre en n rog ycer ne
Withdrawal
Crash 15-30 mins after last dose, can last 3-6 days
Depression, insomnia, irritability, anxiety, suicidal
No treatment
Maintenance
Not usually successful
Desipramine = use and craving Flupenthixol = craving
Amphetamines Indirect-acting sympathomimetic
Displaces mono-amines
st mu ant
Delirium and panic with repeated high doses
Tachycardia, hypertension, and mydriasis
Necrotising arteritis
Can cause hypertensive crisis when combined with MAO-I
Withdrawal = in REM slee de ression and fati ue
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Methyl Xanthines
Methyl Xanthines (caffeine and theophylline) Block adenosine receptors
g oses can oc p osp o es erases c
Also stimulatory action to CO2
Causes cortical arousal
MDMA (ectasy)
Hallucinogen
MOA is unclear
Noted 5-HT pathology in frequent users ( 5-HT cotransporter)
Alters body water dynamics
Adverse effects are similar to acute heat stroke
MI and brain hemorrhage are most important
Other Drugs of Abuse LSD
Psychomimetic which causes sense to be transmuted
Limited abuse because of bad trips
Death trip = meditatio mortis
PCP
May act via opiate receptors
Also blocks NMDA receptors
Reduction in pain, touch, and position sense
Will note vertical and horizontal nystagmus
anna s Uncontrolled laughter, red conjunctiva, reduced fertility, diminished
goal-setting behavior (?? Seriously)
Horizontal only nystagmus
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GHB
Inhibitory to dopaminergic pathways
Used to treat all symptoms of narcolepsy
Increases non-REM sleep
Date-rape drug
Respiratory depressive (major COD)
Also abused by body-builders
Opioids Overdose
Decreased respiration, cyanosis, coma w/ BP
Treatment = naloxone (Carefully!!!)
If methadone must use naltrexone (longer -life)
Withdrawal
Drowsiness, sweating / chills, piloerection
Acute (2 mo) = BP, resp, hyperthermia, mydriasis
Longer = BP, HR, hypothermia, meiosis
Treatment = detox to methadone (or buprenophine)
Maintanence
Naltrexone in already detoxified cancels effects of new dose
Buprenophine is partial agonist at mu receptors
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Barbiturates
Overdose Profound CNS depression
reatment = support ve or resp ratory
CNS stimulents are contra-indicated
Withdrawal
12-24 hours after chronic ingestion
Hypotension, anxiety, seizure (after 72 hrs)
Treatment = pentobarbital or secobarbital
Dilantin (diphenylhydantoin) if history of seizure
Benzodiazepine Overdose
Problem when mixing with EtOH
reatment = umazen to antagon ze enzo tox c ty
Withdrawal
Anxiety, agitation, seizures,
Treatment = flurazepam (or other anti-anxiety med)
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EtOH
Overdose Slurred speech, nystagmus, disinhibited behavior,
=
ThiamineTHEN glucose if necessary
Withdrawal (4-12 hrs after last drink)
Coarse tremor, anxiety, BP, hallucination (tactile / visual)
Overactive ANS = HR, miosis, sweating, fever
Delirium tremens = gross delirium
Treatment = short-acting depressants for symptoms then ween
Maintenance
Disulfiram = blocks aldehyde reductase cuasing adverse effectswith drink