Dr. Mohammad Aljawadi PharmD, Msc, PhD PHCL 478 Clinical Pharmacy Department College of Pharmacy...

ACID-BASE DISORDERS

Dr. Mohammad Aljawadi PharmD, Msc, PhD

PHCL 478

Clinical Pharmacy Department

College of Pharmacy

King Saud University

APRIL 2015

INTRODUCTION Disturbances in acid-base status may be secondary

to, or a cause of, major organ dysfunction As a pharmacist you need to:

Understand and comprehend acid-base physiologyAssess your patients for any acid-base disordersPredict, prevent and recognize drug-related acid-base

disordersRecommend appropriate therapy

INTRODUCTION Acidity of body fluids measured by H+ ions and

expressed as hydrogen ions activity (pH)

pH

Hyd

rog

en

Ion

(n

m/L

)

0

20

40

60

80

100

120

140

6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7Simple and Mixed Acid-Base Disorders: A Practical Approach. Medicine. 1980; 59: 161-187.

As H+ ions increase the pH decrease

ACID-BASE DEFINITIONS Acid, Acidosis and Acidemia

Acids Substance that can release or donate H+

HCl H+ + Cl– H2CO3 H+ + HCO3

–

Acidemia Arterial blood pH < 7.4

Acidosis Excess addition of H+

ACID-BASE DEFINITIONSBase, Alkalosis and Alkalemia

Base Substance that can accept H+

NH3 + H+ NH4+

Alkalemia Arterial blood pH > 7.4

Alkalosis Excess removal of H+

ACID-BASE DEFINITIONSAcidosis always precedes acidemia because the former is the process and the latter is the result

The difference between Alkalosis and Akalemia is similar to acidosis and acidemia

AcidosisThe process of H+ accumulation

AcidemiaBlood pH < 7.4

H2CO3

Non-Volatile Acids

H+ + HCO3–

Volatile Acids

CO2 + H2O

Keto-acidsLactic acids

Organic acids Inorganic acids

Acid-Base Physiology

ACID-BASE PHYSIOLOGY

3

224

HCO

PCOH

]03.0[

][log1.6

2

3

xPaCO

HCOpH

Negative logarithm


Implications:

If CO2 H+ pH

If HCO3 H+ pH


Implications:Once you know two you can calculate the third

Between a pH of 7.2 and 7.5, a pH change of 0.01 units exists for approximately every 1 mEq/L change in [H+]

3

224

HCO

PCOH

ACID-BASE DISORDERS The development of clinical acid-base disorders is

determined by changes in:

The plasma [HCO3–], the so-called metabolic or renal component

ORThe PaCO2, the so-called respiratory component

REGULATION OF ACID-BASE DISORDERS

Three Mechanisms

Buffers

Respiratory

Renal

(Metabolic)

BUFFERS Molecules that accept or donate hydrogen ions

Prevent changes in pH

Effective buffer are the one that has a dissociation constant (pK) near to the body’s pH i.e. 7.4 Is strong acids/base good buffers?

Intracellular (like hemoglobin and phosphate)

Extracellular (Bicarbonate, albumin)

Two main types of buffers Chemical Physiologic

CHEMICAL BUFFERS Bicarbonate

The MOST important buffer in the body [HCO3

-] high in extracellular fluid (ECF)

Acidity of ECF can be regulated by controlling either HCO3-

or PCO2

Dissolved CO2 (PCO2) + H2O H2CO3 H+ + HCO3–C.A.

BICARBONATE Metabolic component of buffer pair

Normal range of bicarbonate = 22-26 mEq/l

Generated and reabsorbed by the kidneys

PHOSPHATE Intracellular and extracellular

Serum inorganic phosphateLow extracellular concentration

Intracellular organic phosphate Important intracellular buffer

PROTEINS Intracellular and extracellular

IC > EC Charged side chains of aminoacids provide buffering

action

Hemoglobin – principle IC protein buffer

HbNH2 + CO2 HbNHCOO– + H+

BUFFERSEarly Chemical buffering

Bicarbonate, phosphate, proteins Control of PaCO2 - Respiratory

Late Control of plasma HCO3

– - Renal


Three Mechanisms

Buffers

Respiratory

Renal

(Metabolic)

PHYSIOLOGIC BUFFERSRespiratory Mechanism CO2 eliminated by the lungs responsible for the

bulk of acid excretion Regulation of CO2

Directly related to metabolic rateNot dependent on substrates ingestedRate & depth of ventilation can be varied

RESPIRATORY MECHANISMS Negative feedback system

Alveolar ventilation rate will increase as pH decreases

3 - 12 minutes response time

Alveolar ventilation

PCO2

[H+]

RESPIRATORY MECHANISMS

– 0.5

– 0.4

– 0.3

– 0.2

– 0.1

0

0.1

0.2

0.3

0.0 0.5 1.0 1.5 2.0 2.5

Rate of alveolar ventilation

pH

ch

an

ge in

bod

y fl

uid

s

Blood pH increases as ventilation rate increases


Three Mechanisms

Buffers

Respiratory

Renal

(Metabolic)

PHYSIOLOGIC BUFFERSRenal Mechanisms Maintain acid-base balance by:

Bicarbonate reabsorption Proximal reabsorption Distal reabsorption

Bicarbonate regeneration Net acid excretion (NAE)

BICARBONATE REABSORPTION

Almost 100% of filtered bicarbonate is reabsorbed dailyReplaces loss during filtration

Two mechanismsProximal bicarbonate reabsorptionDistal bicarbonate reabsorption

Protons are secreted in exchange for sodium

Bicarbonate enters blood through Na+/–HCO3 cotransporter

Luminal sodium-proton pump will pump protons only against a modest concentration gradient

If luminal pH < 6.8 – proton secretion will stop

CA is present inside the cell and on the membrane

Net effect – for every HCO3 removed from tublular fluid, one HCO3 appears in blood

Proximal Reabsorption

H2OCA

Protons are secreted by a proton ATPase pump in the luminal membrane

Bicarbonate enters the blood through the bicarbonate-chloride exchange pump

Proton pump can generate a steep pH gradient Luminal pH = 4.5

CA is present inside the cell, but very little on membrane

BLOOD

LUMEN

HCO3–

Cl–

H+

H++

HCO3–

CO2 + H2O HCO3– + H+

CO2 + H2O

c.a.

ATP

Distal Reabsorption

c.a.From ProximalTubules

BICARBONATE REGENERATIONAlso called Net Acid Excretion (NAE) VERY important buffering system Regeneration replaces bicarbonate losses that

occur during buffering 50-100 mEq of acid excreted in urine daily Two mechanisms

Titratable acid excretionNon-titratable acid excretion

TITRATABLE ACID EXCRETION

Phosphate is the main urinary buffer

Minor buffers – uric acid, creatinine HCO3–

Na+

H+

Na+

HPO42–

H2PO4

LUMINALFILTRATE

REABSORBATEPROXIMAL TUBULE CELL

HCO3–

NON-TITRATABLE ACID EXCRETION

Occurs in the distal tubules

Ammonium is the major by product of amino acid metabolismBicarbonate

reabsorbed and ammonium excreted

2 HCO3–

Na+

2 HCO3--

Na+

2 NH4+

LUMINALFILTRATE

REABSORBATEDISTALTUBULE CELL

Glutamine

Glutamate

2 NH4+

+ AKG2 NH4+

AKG2-= alpha-ketoglutarate

COMPENSATORY RESPONSESChemical Very quick response – almost immediate

Respiratory Quick response – few minutes Maximal effect at 12-24 hours

Kidney Slower response – within hours Maximal effect at 2-5 days

COMPENSATORY RESPONSES [H+] is directly related to PaCO2/HCO3

– ratio

Compensatory responses:Attempts to restore the ratio to normal by altering the

component NOT involved in the primary changeDO NOT completely normalize patient’s pHARE predictable

3

2

HCO

PaCOH

Primarily Alteredin Metabolic

Disorders

Altered byBuffering

Altered by Renal CompensationFor Respiratory

Disorders

Primarily AlteredIn Respiratory

Disorders

Altered by Respiratory

CompensationFor Metabolic

Disorders

]03.0[

][log1.6

2

3

xPaCO

HCOpH

The body tries to keep PaCO2 constant at 40 mmHg and HCO3– constant at 24 mmol/L

LABORATORY ASSESSMENTArterial Blood Gas (ABG) Measures pH, PaCO2, PaO2, SaO2%, HCO3

– pH = 7.35-7.45 PaCO2 = 35-45 mmHg PaO2 = 80-100 mmHg HCO3

-= 22-26 mEq/l SaO2% = > 95% Clinical laboratory measures total CO2 not true HCO3

– HCO3

– is calculated using Henderson-Hasselbalch equation

pH / PaCO2 / PaO2 / HCO3- / SaO2%

Memorize

ARTERIAL BLOOD GASESAdvantages Most frequently ordered test in ICU Can alter treatment plan

Disadvantages Provide intermittent data Often delays Permanent blood loss Pain, vasospasm, tissue damage

Typically displayed in patient’s chart as:

pH / PaCO2 / PaO2 / HCO3–

Or

7.4 / 40 / 98 / 24

ANION GAP

Na+ Cl–

HCO3–

other

Ca2+, Mg2+

K+

Unmeasured anions

Sulfate, phosphate

Organic anions

protein

ANION GAP

Na+ Cl–

HCO3–

Unmeasured anions

ANION GAP

Na+ 148

Cl– 110

HCO3– 16

148 – (110 +16) = 22 Unmeasured anions

ANION GAP

HCO3–

Na+ Cl–

HCO3–

Addition of HClNormal ionogram

Cl–Na+

Cl-

+ H+

AG AG

Addition of lactic acid

CH3COCOO-

+ H+

Na+

HCO3–

Cl–

AG

ANION GAP

Loss of AlbuminNormal ionogram

Na+

Cl–

HCO3–

Unmeasured AnionsAG

Na+

Cl–

HCO3–

Unmeasured AnionsAG

Hypoalbuminemia will decrease the AG by 2.5–3 mEq/L for every 1-g/dL decrease in serum albumin less than 4 g/dL.

LABORATORY ASSESSMENTAnion Gap (AG) Determines the number of unmeasured anions Useful for classifying acidosis

High AG acidosis vs non-AG acidosis Increased AG = retention of unmeasured anions Calculation

Na+ – (Cl– + HCO3–) = normal 10 to 15

OTHER LABORATORY DATASerum Potassium Acidosis

K+ moves out of cell H+ moves into cell

Alkalosis K+ moves into cell H+ moves out of cell

SIMPLE VS. MIXED DISORDERS Simple disorders

Only 1 primary disturbance presentMay have compensatory responses

Mixed disordersGreater than 1 primary disturbance presentCombination of disorders

Exception – cannot simultaneously have respiratory acidosis with respiratory alkalosis

SIMPLE DISORDERS Naming Acid Base Disorders

First Name = Cause (respiratory / metabolic)Second Name = pH (acidosis or alkalosis)

CompensationAttempts to restore the ratio to normal by altering the

component NOT involved in the primary changeDO NOT completely normalize patient’s pHARE predictable

STEPWISE APPROACH TO ACID-BASE1. pH determines acidemia/alkalemia2. Primary process respiratory or metabolic3. Calculate the anion gap4. Check the degree of compensation

CLASSIFICATION Respiratory Disorders (acute & chronic)

AcidosisAlkalosis

Metabolic DisordersAcidosisAlkalosis

http://medlibes.com/entry/acidosis-algorithm

http://medlibes.com/entry/alkalosis-algorithm

CAUSES:

METABOLIC ACIDOSIS/ALKALOSIS

Primary disturbance in HCO3–

Compensation – Change in PaCO2

Metabolic disorder

HCO3- pH Expected Compensation

Acidosis PaCO2

Alkalosis PaCO2

METABOLIC ACIDOSIS Primary cause – HCO3

– Increase in [H+ ] productionLoss of HCO3

– Accumulation and impaired excretion of acids

Classified as High AG or Non-AG Occurs through

Derangements in gut functionDerangements in metabolismExogenous intoxicantsRenal defects

ACIDOSIS

Clinical Presentation Generally nonspecific Respiratory – Hyperventilation CNS – loss of consciousness Cardiac – Contractility decreases

hypotension GI – loss of appetite, N/V Systemic – peripheral vasodilation

CLINICAL PRESENTATION Electrolytes

plasma potassium ( total K+ stores)Chloride – normal or slightly elevatedAnion Gap – normal or elevated

Observed[HCO3–](mmol/l)

PredictedPaCO2

(mmHg)

PredictedpH

Mild > 15 > 30 > 7.32

Moderate 5-15 15-30 7.14-7.32

Severe < 5 < 15 < 7.14

CAUSES OF METABOLIC ACIDOSISElevated AG Retention of unmeasured anions MUDPILES Exogenous Endogenous Defective renal excretion of acid Anion Gap > 20

One gram drop in albumin will lead to a 2.5 drop in normal anion gap

MUDPILES: methanol, uremia, DKA, paraldehyde, iron, lactate, ethylene glycol, salicylates

Reminder

Na+

Cl–

HCO3–

Unmeasured AnionsAG

CAUSES OF METABOLIC ACIDOSISNormal AG Primary loss of bicarbonate Failure to replenish bicarb stores Renal tubular acidosis Normal AG = 10 - 15

COMPENSATION Initial Response

Extracellular buffering by HCO3–

Intracellular buffering by phosphate and proteins Secondary Response

Respiratory Compensation (hyperventilation) Mediated by CNS pH receptors ↓ pCO2 (from normal) = 1.3 times decrease in HCO3

– from the normal value (24 mmol/l)

Winter’s equation: expected pCO2 = (1.5 x HCO3– ) + 8 (with error of ± 2)

Renal H+ excretion (NH4+) Takes 3 – 5 days for maximal effect

FYI

METABOLIC ALKALOSIS Primary cause – in bicarbonate

Net loss of [H+ ]Net gain of alkali (bicarbonate, citrate, acetate)Loss of chloride-rich, bicarbonate-poor fluid

Two typesChloride responsive

Urinary Cl- < 10 mEq/LChloride resistant

CLINICAL PRESENTATION Muscular

Irritability, tetany, hyperreflexia, cramps, weakness CNS

Dizziness, confusion, stupor, seizures, coma Cardiovascular

Susceptibility to arrhythmias (pH > 7.6)Hypokalemic EKG changes

Cellular hypoxia – decreased oxygen delivery

CLINICAL PRESENTATION Electrolytes

in HCO3–

pH and compensatory increase in PaCO2

in Cl– and serum K+

If urinary Cl– < 10 mEq/ml, then chloride sensitive

CAUSES OF METABOLIC ALKALOSISChloride Responsive GI losses Diuretic therapy Posthypercapnia Cystic fibrosis

Chloride Resistant Adrenal disorders Exogenous steroid Profound K+ depletion

FYI

CL-RESPONSIVE=SALINE RESPONSIVE Metabolic alkalosis:

Excess HCO3- If Cl is available in urine,

HCO3- will be secreted in exchange for Cl

Therefore, if saline is given then CL will be filtered through renal tubules and got exchanged with HCO3

Therefore, the net effect will be:Low Cl in urine < 10 mEq/LCorrection of metabolic

alkalosis

FYI

CL-RESISTANT=SALINE RESISTANT

Hyperaldosternism(↑ Aldosterone)

Stimulation Na-K exchangeNa-H exchange

(net result: reabsorption of Na ; excretion of H and K)

Passive excretion of CL with H

Urinary Cl is > 20 mEq/L

Will not respond to saline

administration because H

secretion is main problem

FYI

COMPENSATION Immediate response

Chemical buffering Second response

Respiratory Compensation (hypoventilation) For every 1 mEq/L ↑ in HCO3

– , PCO2 ↑ by 0.6 mmHg Up to PCO2 of 50-60 mmHg

FYI

RESPIRATORY ACIDOSIS/ALKALOSIS

Primary disturbance in PaCO2 Compensation – Change in HCO3

–

Respiratory Disorders

PaCO2 pH Expected Compensation

Acidosis HCO3–

Alkalosis HCO3–

RESPIRATORY ACIDOSIS Primary cause – abnormal CO2

Lungs responsible for maintaining CO2

Fail to excrete metabolically produced CO2

All hypercapnia is abnormalVentilation

Decreased minute ventilation Impaired perfusion

CLINICAL PRESENTATIONUsually due to hypercapnia and hypoxemia CNS

Confusion, stupor, obtundation, coma Cerebrovascular

Vasodilation Headache, intracranial pressure

CardiovascularArrhythmias, tachycardiaDecrease contractility, vasodilation

Hypoxemia

ACUTE RESPIRATORY ACIDOSIS Acute

Rapid onsetDecreased pH, elevated CO2

Hypercapnia develops over few minutes, hours or days Patients are usually uncompensated or partially compensated Marked acidemia

Electrolytes Normal Na+, K+, Cl-

Increased total CO2

CHRONIC RESPIRATORY ACIDOSIS Chronic

Gradual onsetModerate decreased pH, elevated CO2 & HCO3

-

Renal compensation developed Mildly acidemic

Electrolytes Normal Na+, K+, Cl-

PATHOPHYSIOLOGYVentilatory Failure Non-pulmonary causes Pulmonary causes

NON-PULMONARY CAUSES Central drive

Drugs (sedatives, narcotics)Lesions of respiratory center

Neural linkageBrainstem or spinal damage or trauma

Above C5

Respiratory musclesWeakness or fatigue

MiscellaneousOverfeeding with parenterals

PULMONARY CAUSES Acute lung disease

Pneumonia, pulmonary edema, pulmonary embolus, asthma

Chronic lung diseaseCOPD

COMPENSATION Acute

Intracellular bufferingExpected response:

1 mEq/l HCO3– for every 10 mmHg PCO2

ChronicRenal mechanism

H+ excretion and HCO3- reabsorption

Slow adaptation of NH4+and Cl- excretion

Expected response: 3-5 mEq/l HCO3

– for every 10 mmHg PCO2

FYI

RESPIRATORY ALKALOSIS Primary cause – abnormal PaCO2 pH > 7.45 Hyperventilation

CLINICAL PRESENTATIONAssociated with acute disease Cerebrovascular

Vasoconstriction Lightheadedness, confusion, syncope

NeurologicParesthesias, spasms, tetany, cramps, seizures

CardiovascularVasoconstrictionLower arrhythmia thresholdAngina

PATHOPHYSIOLOGYVentilatory Stimulation Arterial hypoxemia

Hypoxemia triggers chemoreceptors Signal medullar respiratory center

Increase ventilatory drive

Direct stimulation of pulmonary sense receptorsWalls of alveoli and airways contain sense receptors

Lung disease

Chemical or physical factorsToxic, pharmacological, mechanical and physical insults

PATHOPHYSIOLOGYClinical Causes Pulmonary Non-Pulmonary

PULMONARY Pneumonia Pulmonary edema Interstitial fibrosis Asthma

NON-PULMONARY Sepsis Liver Disease Salicylate OD Hemodialysis Brain lesions Cyanotic heart disease Pregnancy Psychogenic hyperventilation High altitude

COMPENSATION Acute response

Intracellular buffering2 mEq/L HCO3


Chronic responseRenal retention of H+

bicarbonate reabsorption/net acid excretion5 mEq/L HCO3


KEY POINTS Changes in bicarbonate levels cause

metabolic disturbances Changes in alveolar ventilation cause

respiratory disturbances Lungs and kidneys compensate for changes

in pH Acidosis: increase ventilation (to blow off CO2) and

excreting H+ in the urineAlkalosis: decrease ventilation to increase CO2

levels and excreting HCO3- in the urine

STEPWISE APPROACH TO ACID-BASE1. pH determines acidemia/alkalemia2. Primary process respiratory or metabolic3. Calculate the anion gap4. Check the degree of compensation

MANAGEMENT Correct the

underlying cause

PRACTICE PROBLEMS

ABG Acid-Base disorder

7.4 / 40 / 98 / 24

7.32/30/96/15, Na:144, Cl:110

7.5/45/95/30, Na:144, Cl:110

7.28/46/89/23 Na:144, Cl:110

7.48/30/90/20

A=AG-Metabolic AcidosisB=None-AG Metabolic acidosis C=Respiratory Acidosis D=Respiratory AlkalosisE=Metabolic Alkalosis

QUESTIONS?

Dr. Mohammad Aljawadi PharmD, Msc, PhD PHCL 478 Clinical Pharmacy Department College of Pharmacy...

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