osmosis, osmolarity, edema
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Osmosis, Osmolarity, Edema Molecules move between blood plasma, cells,
and interstitial fluid
Three main compartments
Images: https://courses.lumenlearning.com/nemcc-ap/chapter/body-fluids-and-fluid-compartments/
Classification of Membranes
Permeable impermeable semi-permeable
Cellular plasma membrane is semi-permeable
Osmosis• The biological membranes and cellular barriers
are not permeable for all types molecules
Osmosis• Differentially permeable membrane, same
solvent. Solvent follows solutes, if solutes are not evenly distributed, until extra pressure Posm is created
• Osmotic pressure is the hydrostatic pressure produced by a solution in a space divided by a partially permeable membrane due to a differential in the concentrations of water
• Rule: Water follows solute until either – solute concentrations become equal, or – additional pressure is created in a compartment with
higher combined solute concentration
Osmotic Pressure depends on solute concentrations difference between compartments
• Colligative property. Osmotic pressure depends on the final number of solute molecules, not on their chemical identity
• Water flows to the area where there are more non-water molecules
• Osmotic pressure looks like the gas law formula, where n is the total number of moles of the solute particles
• For V = 1L , Dn/V becomes DM• DM includes all dissociated forms of each
solute
• Posm = DP = Phigher-Plower
PosmV = ΔnsoluteRTPosm = ΔMsoluteRT
Higher pressure : lower pressure
P1V = n1,soluteRTminusP2V = n2,soluteRT
Deriving equation for Osmotic PressureCorrection for solute dissociation (i)
• Propensity of water to follow higher solute concentration is countered by extra work PosmV. V=1L = 10-3 m3
at T=36oC • M is molarity (molar concentration), not mass! • The total M needs to be corrected via van’t
Hoff’s factors, i, i.e. M →i�M if solute dissociates partially
GP =GP0+VΔP
PosmV = −nwRT ln xw= −nwRT ln(1− xstuff ) ≈ nwRTxstuff
Posm = (nstuff /V )RT = ΔMRTPosm[bar]= ΔMRT ≈ 25.7ΔM[bar]
Van’t Hoff factor, i• The number of moles of particles per mole of solute
is the van't Hoff factor, i. If solute does not dissociate (or associate), i = 1
• The original solute molecules may further dissociate• The factor counts the ALL DERIVATIVE FORMS of the
dissolved ingredient, x : molar fraction
• E.g. NaCl results in Na+ and Cl-, x1=0, x2=1 i=2• Example with partial dissolution to three fractions:– 50% monomers, 30% in 2 particles, 20% in 3 particles: i =
0.5 + 2!0.3 + 3!0.2 = 1.7; €
i = x1 + 2x2 + 3x3 + ..
Posm=iDM RT
Examples• The observed lower van’t Hoff factors
illustrate the differences between activities and concentrations. Ions are not fully independent on each other.
Tonicity of extracellular fluids
Isotonic Hypotonic Hypertonic Normal Turgid Plasmolysis
Molarity vs Molality
• Molarity Mi ≡ ni,moles / liter of solution• Mole fraction xi ≡ ni,moles / Sni
• Molality mi ≡ ni,moles / kg of solvent
1 molal solution: 1 mole of solute per 1kg of solvent
xsolute = nsolute/nwater = Msolute /55.5
One liter of pure water contains 55.5 Moles of water molecules (1000g/18g mol-1=55mol)
What Osmolarity is Normal?• Osmolarity of plasma is 285-295 milli-
osmoles/L• I.V.: any fluid > 550 mOsm/L should not be infused
rapidly• The higher the tonicity, the lower should be the rate
of infusion.• Calculated osmolarity in mM units =
2[Na+] + (2[K+]) +[Glucose]+[Urea]+ [Ethanol] ( all [C] in mmol/L)
(glucose mol. mass = 180g/mol: 3.5 – 6.5 mmol/L)– normal range for blood sodium is between 135 and 145
mM/L (different units: 3.10 mg/ml to 3.34 mg/ml)
Seawater osmolarity: ~ 1000 mOsm, do not drink it
Tonicity of intravenous fluids• Osmolality: total solute concentration in a fluid
compartment.• Tonicity: the combined ability of solutes to
produce an osmotic driving force that causeswater to move from one compartment toanother.– Solutes that are capable of moving water are
called “effective osmoles”.– These are solutes that are unable to cross from
the extracellular to the intracellularcompartment: sodium, glucose, mannitol,sorbitol.
– The control of tonicity will determine the normalstate of cellular hydration and cell size. This is ofparticular concern in the case of brain cells.
• Pharmaceutical labeling regulations may require a statement on tonicity.
Non-polar molecules cross membranes:oxygen, carbon dioxide, ethanol
Water, urea use some assistance
Fasting glucose: 4.4 to 6.1 mmol/L(79.2 to 110 mg/dL)
Urea: ~ 3 to 7 mmol/L
Osmolarities of therapeutic solutions or
infusions : examples
• Osmolalities of some intravenous fluids you will encounter during your clinical rotations
• High tonicity of enteralfeeding of premature infants has been implicated in necrotisingenterocolitis (NEC)
https://www.openanesthesia.org/iv-solutions-osmolality/
Normal saline
Lactated Ringers
How to measure osmolarities using boiling or freezing?
• Osmolarities of IV or oral medications can be measured by freezing point depression
• Why?
Boiling and Freezing Points
• Adding solute makes the liquid state more desirable for water because of the entropy increases and the chemical potential becomes lower. If xw is equal to 1 in pure water:
€
Δµwater = RT ln(1− xsolutes) ≈ −RTxsolutesΔSwater _ in _ solution = Rxsolutes
€
µw = µwpure + RT ln xw
Boiling point elevation of a solution
• A solution of solvent (concentration = xsolute ) exhibits a higher boiling temperature than that of pure solvent. Units of xs need to match the units of Kb
DTboiling = Kb xs
Pure solvent: xw = 1, boiling temperature T*
0=D-D * STH vapvap
Solute added: xw < 1, boiling temperature T
€
Δ vapH −T(Δ vapS + Rxsolute ) = 0
€
ΔT⋅ Δ vapS = ΔT⋅ Δ vapH /T = TRxsolute
ΔT = T −T∗ ≈ xsoluteRT∗2
Δ vapH
'
( ) )
*
+ , ,
Pure solvent: xw = 1, freezing temperature T*
Solute added: xw < 1, freezing temperature T
Freezing point depression of a solution
• A solution exhibits a lower freezing temperature than that of pure solvent
DTfreezing = Kf x
€
ΔT = T −T∗ ≈ xsoluteRT∗2
Δ fusH
&
' ( (
)
* + + €
Δ fusH −T∗Δ fusS = 0
€
Δ fusH −T(Δ fusS + Rxsolute )
Osmotic Pumps for Slow Drug Delivery
Semi-permeable
OROS (Osmotic [Controlled] Release Oral [Delivery]
System) is a controlled release oral drug delivery system in the form of a tablet. The tablet has a rigid water-permeable jacket with one or more laser drilled small holes. Water entering the tablet pushes the active drug through the opening in the tablet.
Name (Generic name)Acutrim (phenylpropanolamine)Adalat OROS (nifedipine)Alpress LP (prazosin)Cardura XL (doxazosin)Concerta (methylphenidate)Covera HS (verapamil)Ditropan XL/Lyrinel XL (oxybutynin)Dynacirc CR (isradipine)Efidac 24 (pseudoephedrine, ..)Glucotrol XL (glipizide)Invega (paliperidone)Minipress XL (prazosin)Procardia XL (nifedipine)Sudafed 24 (pseudoephedrine)Tegretol XR (carbamazepine)Volmax (salbutamol)
Some Problems:§ Pressure may be too
high: P ~ 25.7 atm • DM
§ Subject to dose dumping if membrane breaks
counseling patients about not chewing or splitting tablets may be important
§ Slightly more expensive to formulate than coating tablets
§ Possible hole plugging
XL/XR : extended releaseCR : controlled release
Two main liquid body compartments
• Two Main Compartments– Intracellular =
Cytoplasmic (inside cells), ICF : 2/3
– Extracellular (outside cells), ECF : 1/3
• ECF can be further partitioned into blood plasma and interstitium
Total Body Water = WEIGHT x 0.5 (women) or0.6 (men)
Homeostasis
• Definition: Processes by which bodily equilibrium is maintained constant.
• Examples of Bodily homeostasis:• temperature• blood pressure• heart rate• blood glucose level• body fluid composition• Osmolarity• Extra cellular fluid (ECF) volume • Acid-Base balance
Two main interfaces:• tonicity of ICF vs ECF • inside ICF: blood
plasma vs the remaining ECF
Distribution of Solutes in three fluids
K+ in cells
Cells
No albumin in lympth
Na+ in fluids
Plasma vs Lymph: Edema• Edema is defined as soft tissue swelling
due to expansion of the interstitialvolume. Edema can be localized or generalized.
• Some extracellular fluid compartments, a.k.a. trans-cellular fluids (cerebrospinal fluid, intraocular fluid and joint fluid) do not communicate freely with the rest of the body.
Water flow
Albumin+ blood proteins
Less Protein
Cells
Mechanisms maintaining interstitial fluid volume
• Plasma vs Lympth, the role of albumin: 70% of Ponc is due to albumin. Albumin size: ~ 10 nM (100Å)
• Oncotic pressure is a form of osmotic pressure created by plasma protein molecules that are impermeable across the capillary membrane.
• Starling's Law: Hydrostatic Pressure - Oncotic pressure = net fluid movement out of capillary into interstitium.
• P = 120mmHg systolic pressure (+Patm). The smallest pressure in capillaries ~ 20mmHg
60-80 nm• endocrine glands• intestines• pancreas• glomeruli of kidney
30-40 μmAllow cells to pass• Bone marrow• Lymph nodes• Adrenal glands
• < 10 nM• Regular capillaries• CNS (tighter)
Drugs in plasma: protein bindingBlood protein Normal level % Function
Serum Albumins 3.5-5.0 g/dl 55%
create and maintain osmotic pressure; transport insoluble molecules
Globulins 2.0-2.5 g/dl 38% participate in immune system
Fibrinogen 0.2-0.45 g/dl 7% Blood coagulation
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Fibrinogen gets converted to insoluble fibrin during blood clottingEnzymes, Pro-enzymes, hormones, .. < 1%
• Protein binding limits drug concentration, may be used as an “extended-release” mechanism
Human Serum Albumin & Drugs• HSA maintains osmotic/oncotic pressure • C=35 - 50 g/L =3.5 - 5.0 g/dL=0.5-0.75mM • Transports many drugs• Transports thyroid hormones, T3 (Tri-iodo-
thyronine) and T4 (Thyroxine) • Transports other hormones, particularly
fat-soluble ones • Transports fatty acids ("free" fatty acids)
to the liver • Transports unconjugated bilirubin (heme
catabolism, yellow bruises and brown feces)• Competitively binds calcium ions (Ca2+) • Buffers pH
Renal toxin CMPF in drug site 1Stephen Curry
Albumin carries Bilirubin from destroyed heme molecules in the spleen to liver
15-20% of T3and T4 -> HSA(majority by TBG)[ ]
HSA with myristic acid and ketoprofen
26
PDB code: 7jwn
Many cavities, looks like a sponge
Albumin and other drug binding proteins
• HSA MW 67 kDa, 609 amino acids• Half life 20 days (drug half life
extension)• Likes to bind drugs with carboxyls
and/or hydrophobic areas • Other proteins binding drugs
– Lipoprotein– Glycoprotein– α, ß‚ and γ globulins.
• The bound portion may act as a reservoir or depot from which the drug is slowly released in free form.
Hypoalbuminemia• Liver disease (eg cirrhosis)• Excess excretion by the kidneys• Excess loss in bowel (e.g., Ménétrier's
disease)• Wounds and Burns (plasma loss)• Increased vascular permeability• Acute disease states (‘negative prot.’)• Mutations causing analbuminemia• Malnutrition (starvation)
HSA loaded with multiple ligands
Review• Chemical potential of the same molecule in
different phases or compartments (osmosis) must be equal
• Chemical potential of water is lower (better) in solution If xsolutes is small:
• Osmotic pressure: Posm=DMRT, where DM is molarity difference corrected by dissociation, i, osmolarity vs molarity: DM=iDM0
• Osmosis: semi permeable membranes.• Osmolarity and Tonicity: counting solutes that
can not cross the membrane and taking dissociation into account ( i, van’t Hoff’s factor).
• Boiling point elevation• Freezing point depression (Kf does not depend
on solutes!). Kf = 1.858 K kg/mol• Water pressure reduction: Raoult’s law• Gas dissolution in water: Henry’s law• The effects are entropic and to the first
approximation do not depend on the nature of solutes (colligative properties)
€
µw _ in _ solution = µw _ pure + RT ln(xw )Δµw = RT ln(1− xsolutes) ≈ −RTxsolutesΔSw ≈ Rxsolutes
Posm =ΔnsolV
RT = iΔMRT
ΔTboiling = KbxsolutesΔTfreezing = K f xsolutesPw_ vap_ solution = Pw_ vap_ purexwaterPsolute_ in_ gas = KHenry
solutexsolute_ in_water
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