Week 1 Flashcards
what % of total body weight and total body of water is ICF
40% total body weight
2/3 total body of wawter
what % of total body weight and total body of water is ECF
20% of total body weight
1/3 of total body water
of ECF, what % of total body weight is interstitial fluid
15%
of ECF, what % of total body weight is plasma
5%
relative levels of K and Na and major anions in ICF
high in K
low in Na
phosphate and protein
relative levels of K and Na and major anions in ECF
low in K
high in Na
Cl and HCO3
Plasma levels of;
Na
K
Na 150
K 5
ICF levels of;
K
Na
Phosphate
K 160
Na 5
Phosphates 140
with Na/K/ATPase what is the movement of Na and K
3 Na out of the cell
2K into the cell
what is the Na/K/ATPase beta subunit
has no binding sites
what is the Na/K ATPase alpha subunit
intracellular subunit
binding sites for Na and ATP
extracellular binding site for K
Describe Ficks law
the magnitude of the diffusing tendency is proportional to both;
concentration gradient
cross sectional area
and is inversely proportional to the thickness of the membrane
Define osmolarity
number of osmoles per litre of solution
Define osmolality
number of osmoles per kilogram of solvent
what is normal plasma osmolality
290mOsm/l
define mole
the gram-molecular weight of a substance
define molecular weight
the ratio of the mass of one molecule of the substance to the mass of 1/12 of a carbon atom
what is 1 dalton
1/12 of the mass of a carbon atom
define osmole
unti to measure the concentration of osmotically active particles
hyperplasia definition
increase in number of cells to increase the functional capacity as a whole
hypertrophy definition
increase in mass of each cell resulting in larger overall
atrophy definition
shrinkage and loss of structure of cell
increase in autophagic vacuoles
metaplasia definition
a reversible change when one cell type is replaced by another
what metaplasia occurs in barrets oesophagus
squamous to columnar
effects on cell of reversible cell injury
Reduced oxidative phosphorylation –>ATP depletion–>failure of Na/K ATPase pump–> loss of cell membrane integrity –>cellular swelling(ion conc changes)Increased CA2+ intracellularly–> membrane and DNA damage
Defects in protein synthesis–>cytoskeletal damage–>DNA damage
Swelling of ER, loss of ribosomes, membrane blebs
effects on cell with irreversible cell injury
Irreversible mitochondrial injury
Profound membrane disturbance and loss of integrity.
Lysosomes rupture and digest cellular content, swollen mitochondria,
Accumulation of reactive O2 species
nuclear condensation, fading and fragmentation.
Cell death
Morphologic features of Necrosis
Eosinophilic (pink) cells - due to loss of RNA mediated basophilia
Myelin figures - the phospholipid masses that can replace cells when they necrose
Cell and organelle membrane fragment
Nuclear changes
Autolysis
Heterolysis
In necrosis what are the nuclear changes
Pyknosis - small dense nucleus
Karyolysis -faint dissolved nucleus
Karyorrhexis - broken to clumps
6 types of necrosis
Coagulative – architecture preserved eg MI
Liquefactive – liquid viscous mass – in brain hypoxic death, post bacterial infection
Caseous – white, granulomatous, no architecture – TB
Gangrenous – from infection
Fat necrosis – in pancreas
Fibrinoid – Ag-Ab mediated
Physiological types of apoptosis (6)
- Developmental involution
eg thymic atrophy in children - Involution of hormone dependent tissues
eg endometrial breakdown - Homeostasis in normally proliferative tissues
eg intestinal crypt epithelia - Death after purpose finished
eg neutrophils post inflammation - Elimination of self reactive lymphocytes
- cell death induced by cytotoxic T cells
eg virus infected
pathological types of apoptosis (4)
- DNA damage
eg radiation, cytotoxic drugs - Misfolded protein build up
eg mutated genes, free radicals - Infections
eg HIV, adenovirus - after duct obstruction
eg pancreas, parotid
Apoptosis definition
organised cellular death, manifested through activation of an internal suicide program, which leads to orchestrated disassembly of cellular components, designed to eliminate unwanted cells with minimal disruption to surrounding tissue
Morphological features of apoptosis
cell shrinkage
chormatin condensation and fragmentation
cellular blebbing
fragmentation of apoptopic bodies
phagocytosis of apoptopic bodies
lack of inflammation
biochemical features of apoptosis
protein cleavage by caspases
protein cross linking by transgluatminase
cleavage of DNA
plasma membrane alterations
How is the Extrinsic pathway of apoptosis activated/initiated
Death receptor initiated
TNF and Fas receptors on the cell surface contain a death domain
In Extrinsic pathway of apoptosis what activates after the death domain is initiated
Intracellular caspases
particularly Caspase 8
In the extrinsic pathway what happens after caspase 8 is activated
caspase-8 can propagate the apoptotic signal by cleavage of further downstream effector caspases such as caspase-3.
Together with other enzymes induces mitochondria to release pro-apoptotic factors such as cytochrome c resulting in the formation of the apoptosome complex
What happens at the start of the Intrinsic pathway of apoptosis
Mitochondrial outer membrane permeabilisation (MOMP)
causes release of apoptogenic proteins such as cytochrome C, endoG, Smac/DIABLO, AIF-1, and Omi/HtrA2
In the Intrinsic pathway what happens after the release of cytocrome C
leads to its interaction with Apaf-1, allowing the cleavage of procaspase-9,
the formation of the Apaf-1/caspase-9 apoptosome complex, and the subsequent activation of effector caspases
what are the 5 biochemical themes in cellular injury/death
ATP depletion
Irreversible mitochondrial damage
Loss of calcium homeostasis
Oxygen derived free radicals
Defects of membrane stability
How do you calculate loading dose?
Loading dose = Vd x target concentration
How do you calculate maintenance dose?
Dosing rate = clearance rate x target concentration
Divide this my fraction of bioavailability
what is the henderson hesselbalch equation
pH = pKa + log 10 (A- /HA)
describe weak acid
weak acid gives H+
weak acid more lipid soluble at acidic pH
In kidneys weak acid are excreted faster if urine is alkaline
describe weak base
weak base takes H+
weak bases are mor lipid soluble at alkaline pH
In kidneys weak base are excreted faster if urine is acidic
what is EC50
EC50 is dose required for an individual to experience 50% of maximum effect
define ED50
ED50 is the dose for 50% of population to obtain the therapeutic effect
Define Zero order kinetics
the rate of elimination is constant
regardless of concentration of the drug
Define first pass elimination
Drug metabolism in gut wall, in portal blood or most commonly hepatic clearance of drug from portal circulation prior to reaching systemic circulation
what are phase 1 reactions
modifications so a reactive and polar group is added to the drug.
Can occur via oxidation, reduction, hydrolysis, cyclization
what are phase 2 reactions
conjugation.
Drug is combined with charged molecules such as glucuronidation, acetyl, sulfate, glycine.
This aims to detoxify and produces more polar product–> more water soluble and easier to renally excrete
