Week 2 Flashcards
Type I hypersensitivity
Immediate - IgE
Antigen exposure –> Th2 activation –> IL-4 and IgE –> IgE + mast cells –> Release of mediators (After repeat exposure)
Histamine
Immediately released
Late phase (activated mast cell)
Release of prostaglandins and leukotrienes
And Cytokines (TNF-a, IL-4, IL-5)
Type II hypersensitivity
Tissue/organ specific
Antibody/antigen complex –> Complement activation –> inflammation and tissue injury (neutrophils, ROS)
Drug induced hemolytic anemia
Drug (hapten) binds to RBC –> induces pathway for hapten Ab generation –> Ab bind to RBC –> lysis or phagocytosis or complement activated phagocytosis
Occurs when hapten binds to own cell
Grave’s disease
Hyperthyroidism
Antibodies bind to TSH receptor –> constitutive release of thyroid hormones
Can pass from mother to to child
Rheumatic fever
Group A Streptococcal pyogenes
Streptococcal cell wall stimulates Ab response –> antibodies cross react with heart tissue antigens
Type III hypersensitivity
Soluble immune complex - systemic
Complex becomes larger –> complement mediated recruitment of activation of inflammatory cells
Serum sickness - Type III hypersensitivity
Patients given bolus of foreign antibody (against specific disease eg. tetanus) –> antibodies made against antigen –> antigen:antibody complexes form –> type III hypersensitivity
Arthus reaction
Inject antigen –> antigen:antibody complexes form –> complement activation –> inflammation (neutrophil recruitment)
Systemic Lupus Erythematosus
Systemic auto immune disease (Type III hypersensitivity)
Making antibodies against nuclear antigens –> Ag-Ab complexes –> Complement levels decrease –> kidneys affected
Type IV Hypersensitivity (DTH)
Antigen introduced –> Processed by APC –> Th1 recognition –> macrophage activation
CD4 or CD8
Contact hypersensitivity
DTH
Active immunization
Immunized individual acquires immunity to specific antigen
Passive immunization
Preformed antibodies providing temporary protection
T independent antigen
Repeating epitopes that cross link Ig receptors on B cells
Activates B cell without use of T cell
No memory, no H chain switching, no affinity maturation
Conjugate vaccine
Add T-I antigen to carrier protein –> internalized and presented by B cell –> t cell activation –> B cell activation –> Ab secreted
Conjugate vaccine examples
Hib, PCV14, Meningococcal
4 methods of resistance
Enzymatic degradation
Altered target
Decreased uptake
Increased efflux
Concentrated dependent killing
Higher concentration = more rapid, complete cell kill. Decreased resistance
Time dependent killing
Saturation of killing occurs at low multiples of MIC
Cell wall inhibitors
Beta-lactams
Glycopeptides
Cell membrane inhibitors
Daptomycin
Polymyxins
Nucleic acid inhibitors
Fluoroquinolones
Protein Synthesis inhibitors
50S ribosome
30S ribosome
Metabolic inhibitors
Sulfonamides
Trimethoprin
Difference between Penicillins and cephalosporins
Cephalosporins have 6 membered ring, penicillins have 5
Cephalosporins have 2 R groups
Penicillin binding protein
Enzymes that catalyze last step of cell wall synthesis
PBP and Beta lactam
B-Lactam is structurally analagous to D-Ala-D-Ala –> react with PBP and create intermediate so cell wall is not fully synthesized
Beta lactamase
Breaks bond in Beta lactam ring
Molecule disabled
Beta lactamase inhibitor
Binds to beta lactamase so it can’t function
Extends life of beta-lactam drug
Natural penicillin
Narrow spectrum
Streptococci, treponema
Penicillin G, VK
Anti-staphylococcal
Narrow spectrum
Staph-MSSA only
Has beta-lactamses
Amino penicillins
Broad spectrum - Gram+ (not MRSA), some gram(-)
Augmentin
Ureido penicillin
Piperacillin+tazobactam
Very broad spectrum (enhanced gram- incl. Pseudomonas)
1st generation Cephalosporin
Narrow (Gram +)
Staphylococci, streptococci
Cefazolin
Cephalexin
2nd generation Cephalosporins
Broader than 1st gen, includes anaerobes
3rd generation cephalosporin
Broad, enhanced gram-
Pseudomonas
Ceftriaxone - does not cover pseudomonas
4th generation cephalosporins
Very broad spectrum Enhanced gram(-), includes Pseudomonas
Cefepime
5th generation cephalosporins
Ceftaroline
Broad spectrum, MRSA coverage
Binds to altered target site on MRSA
Monobactams
Inhibits gram negatives only
Poor PBP binding of gram+
Penicillin allergies
Carbapenems
Stable to most Beta-lactamases
Very broad, used rarely to avoid resistance
Beta lactam adverse effects: Common
GI: Nausea/loose stools
Taking drug for a while/high doses
Beta lactam uncommon/rare adverse effects
Uncommon: Hypersensitivity - Non IgE mediated rash
Rare: Hypersensitivity - anaphylaxis
Vancomycin
Large, tricyclic glycopeptide
Cell wall inhibitor - binds to D-ala-D-ala so it cant bind to PBP
Step before Beta lactam
Vancomycin spectrum and target
Only active vs gram (+)
Drug of choice for MRSA
Clinical resistance is low
Vancomycin ADME
A: Not absorbed orally
D: Does not cross BBB
M: Negligible
E: Kidney
Monitor drug concentration, keep 10-20ug/mL
Vancomycin toxicity
- Nephrotoxicity
- Red-man syndrome
- Flushing, erythema, angioedema
- Not IgE - Ototoxicity
Daptomycin
Cell membrane inhibitor
Gram(+) via Ca dependent interaction w/membrane
MRSA -
Alternative to Vancomycin
Polymyxins
Binds with negative LPS –> permeability changes, leakage, cell death
Gram(-)
Last resort for MDR-organisms
Polymyxins Adverse Effects
Nephrotoxicity
Neurotoxicity
Topical combination products are safe
Most common Fluoroquinolones
Ciprofloxacin (Cipro)
Levofloxacin (Levaquin)
Moxifloxacin (Avelox)
Gemifloxacin (Factive)
Fluoroquinolone
MoA, Spectrum, Resistance, PK/PD
MoA: Inhibit DNA gyrase and topoisomerase
- blocks DNA replication, inhibit nucleic acid synthesis
Broad spectrum: Gram +/-, atypicals, TB
Oral absorption
Fluoroquinolone adverse effects
GI: Loose stools
CNS: HA, lightheadedness, nervousness
Skin: Photosensitivity
Boxed warning: Tendonitis/rupture, peripheral neuropathy, dysclycemia
Not good for children or prego chicks (unless benefit > risk)
50S ribosomal unit protein synth inhibitor
Macrolides
Oxazolidinones
Lincosamides
Chloramphenicol
30S ribosomal unit protein synth inhibitor
Aminoglycosides
Tetracyclines: Doxycycline
Aminoglycoside/Tetracycline MoA
Bind to 30S ribosome
Prevent binding of incoming charged tRNA
50S subunit drug MoA
Bind to 50S subunit and block peptide bond formation
Macrolides
Azithromycin (Zithromax)
Inhibit protein synthesis
Bacteriostatic, time dependent killing, anti-inflammatory
Low level resistance (efflux pump)
High level resistance (target site modification)
Broad spectrum: Gram+, Neisseria, Treponema
Choice for atypicals
Macrolides clinical use
STI: Chlamydia, Gonorrhea
RTI: Pharyngitis, otitis, CAP
Macrolide adverse effects
GI (higher than most classes)
May increase QTc interval
Erythromycin Drug interactions
P450 inhibitor
Oxazolidinones (Linezolid)
Inhibits protein synthesis at early stage
Narrow spectrum: Gram+
Alt for MRSA
Linezolid Adverse effects
GI
Skin rashes
Serotonin syndrome: SSRI’s use blocked because MAO inhibition by drug
Lincosamide: Clindamycin
50S inhibitor
Broad spectrum: Gram(+), anaerobes, toxoplasma
Adverse effects: Diarrhea, C.difficile colitis
Older drug
Chloramphenicol
50S binding –> block peptide bond formation
Broad spectrum: Gram(+), (-) anaerobes
Chloramphenicol adverse effects
Reversible bone marrow suppression
Aplastic anemia
Gray baby syndrome
Aminoglycosides
Irreversible binding to 30S –> enzyme modification
Spectrum: Gram (-), synergistic activity with gram(+) cell wall agents
High dose, extended interval
Require serum level monitoring
Aminoglycoside toxicity
Nephrotoxicity (5-25%)
-5-7 days
Ototoxicity (1-5%)
Neuromuscular blockade
Tetracycline
Doxycycline, tigecycline (MDR)
Bind to 30S, block initiation complex
Broad spectrum: Gram(+/-)
Tetracycline adverse effects
GI
Photosensitivity
Bad in children
Tetracycline drug interaction
Cations impair absorption
May decrease effect of oral contraceptives
Sulfonamide
Folate inhibitors
Used in combination
Block purine production and nucleic acid synthesis
Broad spectrum: Gram(+/-)
Nitrofurantoin
Inhibits several enzyme systems: Acetyl CoA –> inhibit metabolism
Gram(-) - E.coli
Bladder infections
GI, rash, pulmonary
Guanosine analogs
Acyclovir
Valacyclovir
Famciclovir
Chain termination (inhibits DNA chain elongation)
Genital herpes
Valacyclovir = acyclovir prodrug
Famciclovir: HIgher doses, less frequent
CMV antivirals
Ganciclovir: similar to acyclovir
Valganciclovir (Ganciclovir prodrug)
CMV antivirals adverse effects/drug interactions
GI, insomnia/confusion, rash
Bone marrow toxicity, mutagenic/embryotoxicity
Interact with myelosuppressive agents, seizure potential
Foscarnet MoA, spectrum/use
Inhibits DNA polymerase - pyrophosphate analog
CMV, Acyclovir resistant HSV
Foscarnet Adverse effects/interactions
Nephrotoxicity
Bone marrow toxicity
Electrolyte imbalance
Cidofovir
Cytosine nucleotide analog
Inhibits DNA polymerase
CMV, acyclovir resistant HSV
Cidofovir adverse effects
Nephrotoxicity
Bone marrow toxicity
Carcinogenic, mutagenic
Adamantanes
Influenza antiviral
Inhibit viral uncoating
Influenza A only
Adamantanes ADR
CNS: dizzy, nervous, insomnia
GI
Teratogenic, embryotoxic
Sialic acid analogs
Inhibit viral neuraminidase: clumping of virions
Influenza A/B
Sialic acid analog ADR
Zanamivir: Cough
Oseltamivir: GI
Peramivir: Skin
