Water

• an ideal biologic solvent• a reactant or a product in many metabolic

reactions (excellent nucleophile)• most abundant fluid in the body

04/28/23 1

Physical Properties:1. Strong tendency to form

hydrogen bonds its molecule is an

irregular, slightly skewed tetrahedron with O2 at its center; angle formed between 2 hydrogen is 105˚

acts as a donor of hydrogen to 2 molecules & as an acceptor of hydrogen from 2 more04/28/23 2

Structure of H20

04/28/23 3From Lehninger, 2nd ed., Ch 4

2. Dipole character – refers to the presence of an asymmetric internal distribution of charge in the water molecule

•Strong electronegative O2 atom (pulls e‾ away

from the H⁺ nuclei) = region of partial positive

charge•2 unshared e‾ pairs =

region of negative charge

04/28/23 4

Coulomb’s Law“the strength of interaction (F) between oppositely charged particles is inversely proportional to the dielectric constant (є) of the surrounding medium”Hexane – 1.9Ethanol – 24.3

04/28/23 5

Water – 78.5

3. Good solvent capability – results from its strong tendency to form H-bond with other molecules as well as from its dipole nature

4. Ionization of water – essentially a neutral molecule, water have a slight tendency to ionize; it can act both as an acid & as a basee.g. H2O + H2O < > H3O⁺ + OH‾

hydronium hydroxyl Simple form: H2O < > H⁺ + OH ‾04/28/23 6

Physiologic Importance of Water1. Osmotic function (turgor) – proper

amount inside the cell imparts normal turgor for normal cellular function; proper distension of cells preserves the normal cellular architecture of cellular organelles

2. Transport – delivers nutrients & O2 to the cells; metabolic wastes are carried to organs of excretion

04/28/23 7

3. Protection and lubrication – synovial, pleural, pericardial, & peritoneal fluids; CSF

4. Temperature Regulation – high specific heat, high latent heat of evaporation, and the heat of conductivity of water (unique properties of water)

5. Medium of Ionization – high dielectric constant of water permits oppositely charged particles to co-exist in the cell environment

04/28/23 8

Total Body Water (TBW)

• The body water is distributed between three major compartments:

1. Intracellular sacs2. Interstitium – constitutes the extracellular

environment of the cells3. Vascular space

04/28/23 9

• Regulation of the intracellular volume (ICV) is achieved in part by regulation of the plasma osmolality through changes in water balance; In comparison, maintenance of the plasma volume (PV) (which is essential for tissue perfusion), is closely related to the regulation of sodium balance

• Most important solvent in the fluid composition of living system

• Maintained by several mechanisms that control water intake & output (principally by the kidney)

04/28/23 10

TBW as a percentage of body weight

BIRTH -TBW is 78% of bodywt (kg)1st few mos. – 1 - TBW is 55 – 60% bodywt (kg)Puberty: ♂ - TBW is 60% BW (kg)

♀ - TBW is 55% BW (kg)

TBW (Liters) = 0.61 x wt in kg + 0.251

04/28/23 11

FLUID COMPARTMENTS:TBW consist of:

1. Intracellular fluid (ICF) – 30 – 40% of BW2. Extracellular fluid (ECF) – 20 – 25% of BW

a. Plasma - 4.5 – 5% BWb. Interstitial - 15% BW

3. Transcellular fluid - 2% BW GIT, CSF, Intraocular, Pleural, Peritoneal,

Synovial4. Slowly exchangeable fluid compartment 8 – 10%

Bone, Dense connective tissue, cartilage04/28/23 12

Regulation of TBWExchange of water between cellular & ECF:• Osmotic forces – are the prime determinants

of water distribution in the body. Water can freely cross almost all CMs as a result, the body fluids are in osmotic equilibrium as the osmolalities of the IC & ECF’s are the same.

Expt : OSMOTIC PRESSURE (Glucose, Urea)04/28/23 13

REQUIREMENT FOR WATER2 Major Factors dictate the quantity of water required

by the body:1. The amount needed to give the proper osmotic

concentration2. The amount needed to replace the water lost thru

excretionPlasma osmolality = 285 – 295 mOsm/Kg water

refers to the conc. of solute particles in plasma balance of intake & output

04/28/23 14

INTAKE

Thirst sensation- defined as the conscious desire to drink

water (regulated in the midhypothalamus)- major defense against fluid depletion &

hypertonicity

04/28/23 15

The centers that mediate thirst are located in the hypothalamus (very close to those areas that produce ADH).

The subjective feeling of thirst, which drives one to obtain & ingest water, is stimulated both by PV & by body fluid osmolality.

These are precisely the same changes that (+) ADH production; and the receptors (osmoreceptors & baroreceptors) that initiate the ADH-controlling reflexes are in the same locations as those for thirst. Thirst response is < sensitive than ADH response

04/28/23 16

Angiotensin II – another factor that stimulates thirst (direct effect on the brain); (+) by ECV

Factors Inducing Thirst:1. plasma osmolality by 1 – 2%2. of ECF volume by 10% or more3. angiotensin II

04/28/23 17

Disorders of the Thirst Mechanism:1. Psychologic disorder2. CNS disease3. Potassium deficiency4. Malnutrition 5. Alteration in renin-angiotensin system

04/28/23 18

EXCRETIONObligatory water losses – represents the

minimum vol. of fluid a person must ingest everyday (approx. 1,500 – 2,000 ml/day)

1. Insensible water losses (400 – 600 ml/day)o lungs & skino proportionate to the surface area of the bodyo influenced by body & eventual temperature, RR,

partial pressure of water vapor in the environment

2. Urinary water excretion (800 – 1000 ml/day)o amount of water necessary to excrete a solute load

by the kidney

3. Stool water losses (100 – 200 ml/day)04/28/23 19

PATHWAY by which ADH secretion is increased when PV decreases

PV venous, atrial & arterial pressure plasma ADH ADH secretion

CD permeability to water

water reabsorption

water excretion

04/28/23 20

• Major change caused by water loss/gain out of proportion to Na⁺ loss/gain is in the osmolarity of the body fluids.

• Receptors: osmoreceptors (hypothalamus) (+)

osmolarity ADH secretion

04/28/23 21

SOURCES OF BODY WATERA. Preformed water:

Liquid imbibed as such - 1,200 mlWater in foods - 1,000 ml

B. Metabolic water: - 300 mlWater is produced from the oxidation of foods

in the following amounts:

04/28/23 22

Oxidation of 100 gms Grams of Water

Fat 107 gms

Protein 41 gms

Carbohydrate 55 gms

Normal Routes of Water Gains & Losses in Adults

04/28/23 23

ROUTE ml/day

INTAKE

Drunk 1,200

In Food 1,000

Metabolically produced 350

Total 2,550

ROUTE ml/dayOUTPUT

Insensible water loss (skin,lungs) 900

Sweat 50

Feces 100

Urine 1,500

Total 2,550

Water Equilibrium in Infants

• Maintenance of water balance is less efficient in infants

• Infant – 80% water Adult – 70%• e.g. 7 kgs = 5.6 L water

ICF = 4.2 L ECF = 1.4 L

≈ daily I/O is about 0.7 L (50% of ECF) *for adults: normal water equilibrium has a

turnover equivalent of 17% of ECF

04/28/23 24

Other factors that differ infants to adult:• Surface area volume ratio I > A

≈ > degree of evaporative loss in skin• Immaturity of infant’s kidney

≈ < ability to concentrate urine

04/28/23 25

Disturbance of Fluid BalanceEdema – refers to increase or excessive

accumulation of fluid in the tissue spaces due to increase transudation of fluid from the capillaries.

a. hydrostatic pressure b. oncotic pressure (hypoproteinemia or

hypoalbuminemia) c. cellular overhydration d. dehydration

04/28/23 26

ELECTROLYTESElectrolyte Composition of Body Fluids

Function:a. they contribute most of the osmotically active

particles in the body fluidsb. they provide buffer systems for pH regulationc. they provide proper ionic environment for

normal neuromuscular irritability & tissue function

04/28/23 27

SODIUM

• principal solute (cation) of the ECF• its concentration determines the osmolality of

the ECF• NaCl retention: volume expansion; depletion:

volume contraction

04/28/23 28

Regulation of Sodium1. INTAKE

– its amount in the body is determined by the balance between intake & excretion

– intake depends on dietary custom & personal taste, rather than by physiological needs

– 30 – 300 mmol/day (1.75 – 17.5 gms)

2. ABSORPTION– through the GIT (jejunum)– Mechanism: Na-K ATPase system (augmented by

aldosterone) 04/28/23 29

3. EXCRETION– largely regulated by renal excretion (urine); also in

sweat and feces– renal regulation depends mainly on balance between

glomerular & tubular functions– 99% of Na⁺ is reabsorbed– Na⁺ excretion: Na⁺ excess in the body; Na⁺ excretion: Na⁺ deficit

4. Changes in intravascular volume that redistributes ECF between plasma & interstitial fluid– hypoalbuminemia – transcapillary HP

04/28/23 30

- transcapillary HP- consequences of therapy

Comparison of Na⁺ & H20 Reabsorption Along the Tubules

04/28/23 31

TUBULAR SEGMENTS PERCENT OF FILTERED LOAD REABSORBED (%)

SODIUM WATER

Proximal Tubule 65 65

Descending thin limb of Henle’s loop

- 10

Ascending thin limb & thick ascending limb of Henle’s loop

25 -

Distal convoluted tubules 5 -

Collecting duct system 4 – 5 5 (during water loading); >24

(during rehydration)

HYPONATREMIA • Plasma Na⁺ - <130 mmol/L• may result from abnormal water retention

(dilutional) or primary Na⁺ loss• Causes: - pseudohyponatremia

- hyperlipidemia - hyperproteinemia - osmotic redistribution of water - hyperglycemia

- mannitol, contrast media

04/28/23 32

Reduce Renal Water Excretion

• ARF/CRF• CHF• Nephrotic Syndrome• Cirrhosis of the Liver• Glucocorticoid

deficiency

04/28/23 33

• Hypothyroidism • Antidiuretic drugs• Stress• Inappropriate ADH Secretion • Excessive H20 intake• Compulsive H20 drinking

Excessive Na⁺ Loss Renal : - Mineralocorticoid def.

- Diuretics - Polyuric ARF - Salt wasting renal dses. - RTA

- Metabolic alkalosis - Bartter’s Syndrome

GIT: - Diarrhea DHN - Removal of GI fluid thru suction - Intestinal Fistula - Laxative abuse

04/28/23 34

TRANSCUTANEOUS: - Cystic Fibrosis &

Heart Stress - Heat Losses with

inadequate salt replacement

Sequestration of “third space” losses associated with Inappropriate fluid therapy: a. Burns b. Major trauma (Sx)

• Specific symptoms of hyponatremia (due to cell swelling & cerebral edema): neurologic dysfunction

• Severity of symptom: dependent on magnitude & rate of Na⁺ decline

• symptoms are more pronounced when Na⁺ decreased rapidly & generally do not occur until the sodium is < 120 meq/L

• earliest symptom: anorexia & nausea

04/28/23 35

Management Of HyponatremiaGoal: to increase serum Na⁺ to at least 120 meq/L

over the first 8 – 12 hrs. 1. In edematous states

a. No hypovolemia – diuretics; restriction of salt & fluids

b. With hypovolemia – diuretics; monitoring of fluids; IV albumin

c. Intractable hyponatremia in acidosis - dialysis

04/28/23 36

2. In hypovolemia without edemaa. Replacement therapy i. Required Na⁺ = (135 – serum Na⁺) x TBW*TBW = 50% BW (dehydrated pt) = 60% BW (no dehydration)

ii. Maintenance = 2 – 4 meq/kg/day 3. SIADH

a. Fluid restrictionb. with severe neurological symptoms & very low Na⁺ (<120 meq/L) – 3% NaCl

04/28/23 37

HYPERNATREMIA• Plasma Na⁺ > 150 mmol/L (much less common)• may result from a primary increase in total

body Na⁺ (more frequently from abnormal or non-renal water loss)

04/28/23 38

Causes of Hypernatremia:A. Serum Overload

a. Inappropriate water therapyb. Salt poisoningc. Hyperaldosteronism d. Inadequate water intake

e. Comatose patientsf. Infantsg. Inaccessibility to waterh. Primary adipsia

B. Increase Non-Renal Water Lossa. GIT (diarrhea)b. Insensible (fever)

C. Increase Renal Water Lossa. Hypothalamic diabetes insipidus

i. head traumaii. infarction (Sheehan’s syndrome)iii. degenerative dse.iv. infectiousv. primary idiopathicvi. hereditary (dominant)vii. sporadic

b. Vasopressin resistant DI c. Hypokalemia 04/28/23 39

d. CRFe. Hypercalcemia

i. primary (idiopathic)ii. hereditary (X-linked)iii. sporadic

f. Damage to renal medullai. Sickle cell dse.ii. Nephrolithiasis iii. Renal papillary necrosisiv. Chronic pyelonephritis

g. Essential hypernatremia

04/28/23

• Thirst – is the primary defense against hyperosmolality in hypernatremia.

• Symptoms are primarily neurologic manifestations (cellular dehydration)*as ECF water moves from IC to EC

spaces *serum osmolarity >350 mOsm/L:

restlessness & irritability ataxia & tremors

* at 450 mOsm/L: seizures, intracranial hemorrhage

04/28/23

Management of Hypernatremia• depends on the etiology of the disorder & the

patient’s volume status; generally, will require fluid replacement

1. With dehydration/hypovolemia a. correct hypotension with isotonic saline 20 ml/kgb. correct plasma osmolality slowly by decreasing

serum Na⁺c. maintenance – amount of H20 & Na⁺ need to be

reduced by 25% as ADH levels would be high2. With overhydration

a. normal renal function – diureticsb. poor renal function – dialysis

04/28/23

POTASSIUM

• principal cation of the ICF• 160 meq/L (muscle)• conc. in the ECF = 4 – 5 meq/L

04/28/23

Regulation of Potassium1. INTAKE – recommended daily intake: 1 – 2 meq/g BW;

Na⁺ intake tends to be higher, so the Na⁺/K⁺ ratio in the diet exceeds 1.

2. ABSORPTION – complete in the upper GIT3. EXCRETION – K⁺ output balances intake

*kidney – major organ responsible for maintaining K⁺ balance*filtered K⁺ is reabsorbed almost entirely in the proximal segments of the nephron; urinary K⁺ is derived predominantly from distal secretion*factors enhancing secretion & excretion: diuretic aldosterone, dietary K⁺ , alkalosis, distal tubular flow rate

04/28/23

Tubular Potassium TransportNORMAL OR HIGH

K⁺ DIETLOW K⁺ DIET OR K⁺ DEPLETION

Proximal Tubule Reabsorption (55%) Reabsorption (55%)

Thick Ascending Limb Loop of Henle

Reabsorption (30%) Reabsorption (30%)

DCT & CD (Cortical) Secretion Reabsorption

CD (Medullary) Reabsorption Reabsorption

04/28/23

Mechanism of K Secretion in the Cortical CD

• transcellular K⁺ secretion: principal cells of the cortical CD

• K⁺ is actively moved into the cell by the basolateral membrane Na-K-ATPase pumps and then diffuses across the luminal membrane through these K⁺ channels

• both reabsorption of Na⁺ & secretion of K⁺ by these cells are regulated by aldosterone

04/28/23

HYPOKALEMIA

• produced by a shift of K from the EC to the IC and or actual loss in our body

• serum K < 3 meq/L

04/28/23

Causes of Hypokalemia:A. Extra-renal etiologies1. Inadequate intake of K

i. actual (fasting, anorexia nervosa)ii. relative (rapid in cell mass, complication of

treatment for megaloblastic & Fe def. anemia, transfusion with frozen RBC)

2. Excessive sweating3. GIT losses

i. diarrheaii. ingestion of K-binding clay (geophagia)iii. laxative abuse

04/28/23

B. Renal etiologies1. RTA2. DKA3. Bartter’s syndrome4. Mineralocorticoid excess5. Glucocorticoid excess6. Magnesium depletion

i. antibiotic therapyii. leukemiaiii. diuretic

7. Transcellular shiftsi. alkalosisii. insulin excessiii. intoxication (Theophylline, Ba)

8. Hypokalemia – periodic paralysis04/28/23

Clinical Consequences of Hypokalemia1. Cardiac – sensitivity to digitalis toxicity,

arrythmias2. Neuromuscular – constipation, weakness,

rhabdomyolysis 3. Renal – interstitial nephritis4. F & E – polyuria, polydipsia, etc.5. Endocrine - aldosterone, plasma rennin,

insulin6. Hemodynamics - BP, pressor response to

angiotensin & ADH04/28/23

Management of Hypokalemia

1. Oral route – if hypokalemia is not severe2. Parenteral – preparation – KCl: 1 meq/ml (needs ECG monitoring)

04/28/23

HYPERKALEMIA • defined as serum K level >5.5 meq/LCauses of Hyperkalemia:A. Spurious hyperkalemia

1. Ischemic blood drawing2. Hemolysis3. Abnormal RBC 4. Thrombocytosis5. Leukocytosis

04/28/23

B. Transcellular shifts1. Acidosis2. Insulin def.3. β-adrenergic blockade4. Exercise

5. Digitalis intoxication6. Fluoride intoxication7. Hyperkalemia periodic paralysis

C. Renal Causes – Renal failureD. Aldosterone deficiencyE. Drug-induced syndromes (ACE inhibitors, heparin, cyclosporine)F. Primary tubule dysfunction

04/28/23

Clinical Manifestations of Hyperkalemia

1. Cardiac – ECG changes: peak T wave, flattening of P, prolonged PR interval, widened QRS complex, complete heart block, ventricular fibrillation, cardiac arrest

2. Neuromuscular – parethesias, weakness, flaccid paralysis

04/28/23

Management of Hyperkalemia

1. Sodium bicarbonate MOA: shift K into the cell2. Calcium gluconate MOA: stabilize membrane

potential3. Glucose & insulin MOA: stimulates cellular

uptake of K4. β-agonist MOA: stimulates cellular uptake of K5. Kayoxalate MOA: exchange Na for K across the

colonic mucosa

04/28/23

CALCIUM• approx. 99% of the body Ca is in the bone• exists in 3 general forms:a. Complex Ca (15%) – bound to anions (PO4, citrates, &

HCO3)b. Protein-bound Ca (40%) – usually with albumin

a in albumin conc. of 1 gm/dl results in a in total Ca conc. of 0.8 mg/dl

binding of Ca to albumin is pH dependentan acute inc. or dec. in pH 0.1 unit will inc. or dec. respectively protein

bound Ca by about 0.12 mg/dle.g. inc. pH (alkalosis) inc. Ca binding dec. ionized Ca tetany

c. Ionized Ca (45%) – only biologically active form in nerve, muscle, & other target organs

04/28/23

MAGNESIUM

• 4th most abundant cation in the body• plays a role in cellular enzymatic activity

(glycolysis & ATPase stimulation)• 60% in bone; 40% IC

04/28/23 57

ACID-BASE BALANCE• ECF component, H⁺ ion conc. is maintained

within narrow limits (40 nanomol/L)• regulation of H⁺ ion conc. at this low level is

essential for normal cellular function bec. of the high reactivity of H⁺ ions, particularly with proteins this property is related to the relatively small size of the hydronium ion (hydrated form of H⁺ ion), in comparison with that of Na⁺ & K⁺ ions

≈ H⁺ ions are more strongly attracted to the negatively charged portions of molecules & are more tightly bound than Na⁺ & K⁺ ions

04/28/23 58

• when there is a change in the H⁺ ion conc. proteins gain/lose H⁺ ion = result in alteration in charge distribution, molecular configuration, & consequently protein functione.g. rate of glycolysis = H⁺ ion

(measured by rate of lactate production)

• this change in cellular metabolism is mediated by a similar inverse relationship between the H⁺ ion conc. & the activity of several glycolytic enzymes (phosphofructokinase)

04/28/23 59

Three Basic steps of H⁺ ion regulation:1. Chemical buffering by the EC & IC buffers2. Control of the partial pressure of CO2 in the

blood by alterations in the rate of alveolar ventilation

3. Control of the plasma HCO3 conc. by changes in renal H⁺ ion excretion

04/28/23 60

“An acid is a substance that can donate H⁺ ion and a base is a substance that can accept H⁺ ion”. These properties are independent of charge….(Bronsted)

04/28/23 61

• There are 2 classes of physiologically important acids: carbonic acid & non-carbonic acid.

• Important, because of the different rates of production & routes of elimination.*Each day, the metabolism of carbohydrates & fats

results in the generation of approx. 15,000 mmol of CO2 combines with H2O = H2CO3

*mech. loss of CO2 via respiration• Non-carbonic acids – primarily derived from the

metabolism of proteins.*Oxidation of sulfur contg. AAs results in the

generation of H2SO4 (approx. 50 – 110 meq/day)*mech. excretion in urine

04/28/23 62

Forms of Acid & Bases1. Simple acids & bases – these are cpds with a

single weakly acid or basic group2. Ampholytes – these are molecules that

contain groups with both an acidic & basic pKa (e.g. AA)

3. Polyampholytes – these are large molecules with many acid & basic groups (e.g. proteins)

4. Polyelectrolytes – these are macromolecules that carry multiples of only one kind of charge either cationic or anionic (e.g. NA)

04/28/23 63

pH

• pH= -log [H+]• increasing the amount of H+ (in an acidic

solution), decreases the pH• increasing the amount of OH-decreases the

amount of H+ (in a basic solution), therefore, the pH increases

• pH< 7 acidic• pH>7 basic

Conjugate Base Pairs

• Whatever is produced when the acid (HA) donates a proton (H+) is called its conjugate base (A-).

• Whatever is produced when the base (B) accepts a proton is called a conjugate acid (HB+).

Conjugate Base Pairs • HA(aq)+ H2O(l) H3O+(aq)+ A–(aq)

Acid Base conjugate acid conjugate base

• Water exhibit a tendency to dissociate:*

• differ by one H+ for acids/bases• Example: HC2H3O2 and C2H3O2

-

acid conj. base

Ionization of water

• Although neutral water has a tendency to ionize

H2O <-> H+ + OH-

• The free proton is associated with a water molecule to form the hydronium ion

H3O+

• High ionic mobility due to proton jumping

Proton Jumping Large proton and hydroxide mobility

• H3O+ : 362.4 x 10-5 cm2•V-1•s-1

• Na+: 51.9 x 10-5 cm2•V-1•s-1

• Hydronium ion migration; hops by switching partners at 1012 per second

Kw

Kw = [H+][OH-]• Where Kw is the ionization constant

of water• For pure water ionization constant is

10-14 M2 at 25ºC• For pure water

[H+] = [OH-] = (Kw)1/2 = 10-7 M

Acids and bases• For pure water (neutral)

[H+] = [OH-] = (Kw)1/2 = 10-7 M

• Acidic if [H+] > 10-7 M• Basic if [H+] < 10-7 M

Acids and Bases

Lowery definition:• Acid is a substance that can donate a proton.• Base is a substance that can accept a proton.

HA + H2O H3O+ + A- /OH-

Acid Base Conjugate Conjugate Acid Base

or

HA A- + H+

Acid Conjugate Conjugate Base Acid

If you establish equilibrium, changes in [H+] will shift the ratio of HA and A-.

By adding more H+ , A- will be consumed forming HA.

If there is sufficient [A-], the extra H+ will also be consumed and the [H+] will not change.

AHHA

Acid strength is specified by its dissociation constant

Molar concentration

for: HA + H2O H3O+ + A-

• reactants products HA H3O+

A- H2O

a measure of relative proton affinities for each conjugate acid base pair.

O][H]HA[]][AO[H

2

-3

aK

These ratios are

What to do about the water!The concentration of H2O remains almost unchanged especially in dilute acid

solutions.

What is the concentration of H2O?

Remember the definition: Moles per liter

1 mole of H2O = 18 g = 18 ml

1000 g/litermlg 11

Mmolgg 5.55

/181000

][]][[][ 2 HA

AHOHKKa

From now on we will drop the a, in Ka

Weak acids (K<1)

Strong acids (K>1)

Strong acid completely dissociates: Transfers all its protons to

H2O to form H3O+

HA H+ + A-

Weak Acids

Weak acids do not completely dissociate: They form an equilibrium:

HAHAIf we ADD more H+, the equilibrium shifts

to form more HA using up A- that is present.

Dissociation of H2O OHHOH 2

Water also dissociates [H2O] = 55.5

][]][[

2OHOHHK

214 M10]][[ OHHKw

Ionization constant for water

Since there is equal amounts of [H+] and [OH-]

M10x1][][ 7 OHHThis is neutral

At [H+] above this concentration the solution is ACIDIC

At [H+] below this concentration the solution is BASIC

9101][ xH

[H+] pH

10-7 = 7

10-3 = 3

10-2 = 2

10-10 = 10

5x10-4 = 3.3

7x10-6 = 5.15

3.3x10-8 = 7.48

pH = -Log[H+]

It is easier to think in log of concentrations but it takes practice!!

Henderson - Hasselbalch equation

][]][[

HAAHK

From

][][][

AHAKHRearrange

Take (-)Log of each][][loglog

HAAKpH

][][log

HAApKpH

Above and below this range there is insufficient amount of conjugate acid or base to combine with

the base or acid to prevent the change in pH.

[HA]][Alog pK pH

-

110

101 from variesratio

]HA[][A

Relationship of pH to structure

• We can think of a weak acid, HA, as existing in two forms.– Protonated = HA⁺– Deprotonated = A-

• Protonated is the acid• Deprotonated is the conjugate base

– Titrated form

Relationship between pH and [H+] / [OH-] concentration

Observation

If you add .01 ml i.e 1/100 ml of 1M HCl to 1000 ml of water, the pH of the water drops from 7 to 5!!

i.e 100 fold increase in H+ concentration: Log = 2 change.

Problem:Biological properties change with small changes in pH, usually less than 1 pH unit.

How does a system prevent fluctuations in pH?

Buffers

A buffer can resist pH changes if the pH is at or near a weak acid pK value.

Buffer range: the pH range where maximum resistance to pH change occurs when adding acid or base. It is = +1 pH from

the weak acid pK

If pK is 4.8 the buffering range is 3.8 5.8

Why?

The buffer effect can be seen in a titration curve.

To a weak acid salt, CH3C00-, add HC1 while monitoring pH vs. the number of equivalents of acid added.

ordo the opposite with base.

Buffer capacity: the molar amount of acid which the buffer can handle without significant changes in pH.

i.e

1 liter of a .01 M buffer can not buffer 1 liter of a 1 M solution of HClbut1 liter of a 1 M buffer can buffer 1 liter of a .01 M solution of HCl

Distribution curves for acetate and acetic acid

Titration curve for phosphate

Table 2-3

Dissociation constants and pK’s of Acids & buffers

Acid K pK

Oxalic 5.37x10-2 1.27H3PO4 7.08x10-3 2.15Succinic Acid 6.17x10-5 4.21 (pK1)Succinate 2.29x10-6 5.65 (pK2)H2PO4

- 1.51x10-7 6.82NH4

+ 5.62x10-10 9.25Glycine 1.66x10-10 9.78

What is the pH of a solution of that contains 0.1M CH3C00- and 0.9 M CH3C00H?

What is the pH of a solution of that contains 0.1M CH3C00- and 0.9 M CH3C00H?

1) pH = pK + Log [A-] [HA]

2) CH3C00H CH3C00- + H+

3) Find pH

4) pK = 4.76 A- = 0.1 M HA = 0.9 M

5) Already at equilibrium

6) X = 4.76 + Log 0.1 0.9

Log 0.111 = -.95 X = 4.76 + (-.95) X = 3.81

Mechanisms of pH Regulation1. Neutralization of buffer systems in the blood,

lymph, interstitial fluid & ICF2. Bicarbonate buffer system3. Phosphate buffer system4. Plasma protein buffer system5. Hemoglobin buffer system6. Regulation of CO2 excretion by the lungs7. The excretions of acids & bases by the kidney8. The synthesis of ammonia by the kidneys 04/28/23 94

Buffer Systems in the Body1. Bicarbonate Buffer System (BBS) – major

buffer system of the ECF responsible for the neutralization of fixed acids- sometimes known as the “alkali reserve of the body”- serves as the first line of defense, and as such any treat to the acid-base equilibrium of the body will be reflected in the BBS

04/28/23 95

2. Phosphate Buffer System – major IC buffer system and is also active in the renal elimination of acids

3. Plasma Protein Buffer System – plays a minor role in the buffering process in the plasma

4. Hemoglobin Buffer System – 2nd buffer system in the plasma which accounts for the neutralization and eventual disposition of 60% of CO2 in the lungs

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Role in the Kidney• Kidney – contributes to the homeostasis of the

ECF H⁺ ion by regulating plasma HCO3⁻ conc. • 2 mechanisms:1. Excretion of filtered and/or secreted HCO3⁻2. Addition of new HCO3⁻ to the blood flowing

through the kidneysIn response to a plasma H⁺ ion conc. (alkalosis) kidneys will excrete large quantities of HCO3⁻ in the urine. In response to a in plasma H⁺ ion conc. (acidosis) kidney do not excrete HCO3⁻ in the urine, instead add new HCO3⁻ conc. to the blood

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I. HCO3⁻ FILTRATION, REABSORPTION, & SECRETION

• HCO3⁻ is completely filtered in the renal corpuscles, its reabsorption is an active process which involves tubular secretion of H⁺.

• H⁺ secretion occurs mainly in the proximal tubule, thick ascending limb Loop of Henle, and CD system (type A intercalated cells)

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LUMEN RENAL TUB. CELL INTERSTITIUM

H20 + C02

carbonic anhydrase

HCO3⁻ HCO3⁻H⁺

H⁺HCO3⁻ +

H2CO3H2CO3

H20 + C02

Note: proximal tubule – reabsorbs 80% of filtered HCO3⁻ Thick ascending limb – reabsorbs 10 – 15% of filtered CD & DCT – 5 – 10% reabsorption

II. ADDITION OF NEW HCO3⁻ • the effect of adding new HCO3⁻ to the body is of

course to alkalinize it, and this is the renal compensation of acidosis.

• Two Mechanisms:1. Secretion of H⁺ ions, instead of causing HCO3⁻

reabsorption, are excreted in the urine, combined with non-HCO3⁻ buffer supplied by filtration

2. Catabolism of Glutamine to yield NH4⁺, followed by excretion of NH4⁺ in the urine

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LUMEN RENAL TUB. CELL INTERSTITIUM

H20 + C02

carbonic anhydrase

HCO3⁻ HCO3⁻H⁺

HPO4

H2CO3HPO 4⁻

H2P04

Note:

A. Secretion of H⁺ ions Non- HCO3⁻ buffer most important is phosphate/ HPO4⁻ (dibasic PO4)

+ H⁺

Urine Acidification

New alkalinizing the blood

H2P04⁻ = 80% filtered in the glomerulus

75% is reabsorbed 25% available for buffer

B. Glutamine Catabolism plus NH4 Excretion

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LUMEN TUBULAR CELL INTERSTITIUM

GLUTAMINE GLUTAMINE GLUTAMINE

GLUTAMATENH4 +

α-Ketoglutarate

2HCO3

CO2 + H2O

2HCO3new HCO3

NH4

NH4Cl +

NaCl Na

NH4Cl

Acidogenous salt

excreted

Note: one Glutamine = 2 NH4 plus 2 H2CO3

Disturbance in Acid-Base Balance

Normal Values:Plasma pH = 7.35 – 7.45 pCO2 = 35 – 45 mmHgpO2 = 60 – 100 mmHgHCO3 = 22 – 28 meq/L (A)

21 – 23 meq/L (NB)

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• Acidosis – is defined as a disturbance that tends to add acid or remove alkali from the body fluids

• Alkalosis – any disturbance that tends to remove acid or add base

• 2 types of Acid-Base disorders:a. Respiratory b. Metabolic*primary resp. disorders – affect blood acidity by

causing changes in the pCO2

*primary met. disorders – are caused by disturbances in HCO⁻3 conc.

*primary disturbances are usually accompanied by compensatory changes

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METABOLIC ACIDOSIS

• pH, HCO⁻3, non-volatile acids• characterized by a primary in HCO⁻3 & pH

and a compensatory pCO2

• Mx: (with severe degree of academia, <pH 7.2)

= NaHC0⁻3 1 – 3 meq/kg

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METABOLIC ALKALOSIS• pH, HCO⁻3, loss of organic acids• this results from the addition of alkali or loss

of acid and is maintained by a renal elimination of HCO⁻3

• Respiratory compensation (hypoventilation) is limited by hypoxia

• Mx: seldom indicateda. isotonic HCl or 0.1M NH4Clb. Acetazolamide

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RESPIRATORY ACIDOSIS

• pH, pCO2

• results from alveolar ventilation & subsequent hypercapnia

• Renal compensation takes days to reach maximal levels

• Mx: improving ventilation

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RESPIRATORY ALKALOSIS• pH, pCO2

• this is characterized by low pCO2, high pH and a compensatory low serum HCO⁻3

• Hyperventilation is the primary underlying cause of this disorder

• Mx: optimize oxygenation; reassurance

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