Week1 Flashcards
Weak acid
Ampicillin/aspirin
Stomach absorption
Uncharged permeable
Weak base
Amiodarone
Intestine absorption
Bioavailability
Efficiency of delivery to systemic circulation
Fraction of dose in systemic circulation in unchanged form
Affected by metabolism & excretion
First pass effect
Amt of drug eliminated by metabolism before systemic circulation
Determines bioavailability
Enteral administration
Oral
Rectal
Sublingual
Buccal
Parenteral administration
Intravenous Subcutaneous Intramuscular Topical/transdermal Pulmonary Intrathecal
IV bioavailability
100%
Most rapid onset
Phase I reactions
Parent drug to polar metabolite
(-OH, -NH2, -SH)
Inc water solubility
Reduction in activity
Phase II reactions
Polar substances conjugated to endogenous polar substances (glucuronic acid, sulfuric acid, acetic acid, glycine)
Highly polar
Highly water soluble
Completely inactive
Enzyme Induction
Repeated substrate administration —> inc isoform metabolite compound —> inc metabolism of isoform substrates
CYP2D6 polymorphism
Debrisoquin/4-hydroxydebrisoquin ratio
(P-450 substrate)
Low ratio gene duplication (ultrarapid)
High ratio null mutation (poor)
Slow acetylators
Ar
Slow acetylation of anti-Tb drug isoniazid
CYP2C9
Lower affinity for warfarin substrate
Bleeding risk
TPMT*3
TPMTL phenotype
Test for allele before starting leukaemia treatment
Use reduced dose in treatment
Leukocytes
Granulocytes:
Neutrophils
Eosinophils
Basophils
Agranulocytes/mononuclear cells:
Lymphocytes
Monocytes
Azurophilic granules
Primary Produced first in cell differentiation Present in all leukocytes Contents: Myeloperoxidase Cationic proteins BPI (damages G- bacteria) Lysozyme (G+) Defensins Elastase
Specific granules
Secondary Made later in differentiation In granulocytes Contents: Lysozyme Lactoferrin (competes w bacteria for Fe/Cu) Collagenase
TLRs
Toll-like receptors (PRRs)
Bind to PAMPs on pathogens (direct binding)
Fc-are
For IgG (opsonin) —> binds to bacteria Indirect : neutrophil bonds to Fc portion of IgG Ab post-opsonisation
Sterilization
All forms of microbial life killed (incl spores)
Disinfection
Kill most infections agents on inanimate surfaces
Fail to kill spores, mycobacterium, Hep Virus
Sanitation
Lower # of bacteria to safe levels
Food industry
Antiseptics
Prevent microorganism growth on living tissue
Temporary: recolonisation from pores & ducts
Pasteurization
Heat (62C/30mins or 74C/3-5mins) to kill pathogenic bacteria often found in milk (salmonella, mycobacterium, listeria, streptococcus, brucella, campylobacter)
Doesn’t kill spores
Reduce bacterial content by 97-99%
Germicide
Kills microorganisms (bacteriocide) Sporicides: kill spores Viricide: viruses Fungicide: fungi Tuberculocide: mycobacteria
Pyrogens
Microbe-derived contaminants that cause fever
Via dead bacteria (LPS)
Low MW, survive filtration and autoclaving
Pyrogen free= never any microbial growth
Transformation
Free donor DNA (fragment or plasmid) taken you by competent recipient
From later cells, occurs naturally
Transfection
Donor DNA is bacteriophage
Transformation + infection
Transduction
Donor DNA carried to recipient in phage capsid
Generalised vs. Specific
Conjugation
Transfer via conjugation F/R Plasmid
Tra gene
Donor keeps copy (rolling circle replication)
Coagulative Necrosis
Dead tissue architecture
Enzyme denaturation—> eosinophilic cells no nuclei
WBC phagocytosis
Infarct
Liquefactive Necrosis
Focal bacterial/fungal infection
Neutrophils and macrophages degrade
CNS hypoxic injury
Pus (dead WBCs/debris)
Gangrenous necrosis
Loss of blood supply: coagulative necrosis (dry)
+ bacterial infection: liquefactive necrosis (wet)
Caseous Necrosis
Cheeselike central granuloma
Tuberculosis & infections
Pink, amorphous, granular
Fat necrosis
Pancreatic lipase release Breast trauma Fat + calcium = soap (dystrophic calcification) Chalky-white Normal serum Ca2+
Mitochondrial Damage
- Permeability pore: ox phos fail—> dec ATP
- ROS formation
- Proteins released (cytochrome c): activate caspases
Free radical effects
Lipid peroxidation
Oxidative protein modification
DNA lesions
Point of no return
Inability to reverse mitochondrial dysfunction
No ox phos and dec ATP
Membrane function disturbances
Metabolic Derangement Pathways
- Inadequate removal via packing/transport deficit
- Abnormal endogenous substance
- Storage diseases
- Abnormal exogenous substance
Granulocytes
Specific granules
Azurophilic granules
Lobulated nucleus
Agranulocytes
Mononuclear leukocytes
Azurophilic granules
No specific granules
Non-lobulated nucleus
Neutrophils in acute inflammation
Leukocytosis
Shift to the left
Cross-linked IgE basophil activation
- Degranulation (histamine, heparin sulfate, ECF, NCF)
- Cytokines synthesis (IL-4, IL-3)
- Membrane phospholipid cleavage (arachadonic acid pathway)
Type I Hypersensitivity Response
Hay fever
Asthma
Hives
Anaphylaxis
Small Lymphocytes
6-8 microns
90% of lymphocytes in blood, 70% T cells
Nucleus: RBC size, kidney/round shape, heterochromatic
Sky blue cytoplasm rim
Large lymphocytes
Via Blast transformation 30 microns Dichromatic nucleus Smudged chromatin More cytoplasm
PAMPs
LPS (G-) Peptidoglycan/lipotechoic acid (G+) Unmethylated CpG (bacterial DNA) dsRNA (viruses) Glycolipids/lipoprotein (bac, fungi, paras)
DAMPs
Intracellular: HSP HMGB1 S100 Hyaluronan
Non-protein: ATP Uric acid Heparin sulfate DNA
PRRs
Innate immune system R for PAMPs/DAMPs Germ line encoded Limited repertoire On all cells of same lineage Cell associated & soluble
Resident macrophage
Clean up/homeostasis
Kupfer, alveolar, osteoclasts, microfilm, mesangial, sinusoidal
Inflammatory macrophage
M1 Blood —> tissue Arrive after neutrophils Activated by: INF-y, TNF, LPS, microbes Inhibited by: IL-13, IL-4, IL-10 Makes: ROS, NO, enzymes (microbicidal); IL-1,12,23, chemokines (inflammation)
Alternatively activated macrophages
M2 Downregulate inflammation —> repair Makes TGF-B, IL-10 (anti inflammatory) & GFs (tissue repair) Not antimicrobial Induced by: IL-4, IL-10, IL-13 Inhibited by: TNF, LPS, microbes, IFN-y
IFN-y
Type II Interferon
T cells & NK cells
Recruits/activates macrophages
Stimulates adaptive immune response
Intrinsic Apoptosis
Outer membrane permeability Cytochrome C BCL2 proteins Cell injury: GF withdrawal, DNA damage, protein misfolding Activated caspase 9
Extrinsic apoptosis
TNF-R death domain
Fas (CD95)
FasL on T cells
Fas-FasL: FADD —> binds & activates caspace 8 / 10
Labile cells
Continuously dividing
GI epithelium, hematopoietic cells
Stem cell pool
Not totipotent
Stable cells
Quiescent
Kidney, liver, pancreas, SM, lymphocytes
Permanent cells
Non dividing after injury
Neurons, cardiac m, skeletal
Angiogenesis
VEGF & NO Pericyte detachment BM degradation Endothelial cell migration & proliferation Periendothelial cells are recruited BM deposited
Nutrition & wound healing
Protein
Vit C
Copper
T III —> T I collagen (collagenase MMP + Zinc)
First intention healing
D1 coagulation - fibrin, neutrophils
D2 epithelial cells & BM
D3 macrophages, fibroblasts, nearly thick epidermis
D5 neovascularization peak - granulation tissue
Wk2 fibroblasts & collagen
Mo1 cellular CT scar
Second intention healing
Large wound, edges not in contact
Myofibroblast wound contraction over 6wks
Wound Strength
D7 10% strength low collagen
D60-70 100% collagen, 30% strength (TIII)
3mo 100% collagen, 70-80% strength (inc TI)
Never reaches 100%
