dr. mohammad aljawadi pharmd, msc, phd phcl 478 clinical pharmacy department college of pharmacy...
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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
ACID-BASE PHYSIOLOGY
Implications:
If CO2 H+ pH
If HCO3 H+ pH
ACID-BASE PHYSIOLOGY
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)
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
REGULATION OF ACID-BASE DISORDERS
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
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
REGULATION OF ACID-BASE DISORDERS
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
– for every 10 mmHg PCO2
Chronic responseRenal retention of H+
bicarbonate reabsorption/net acid excretion5 mEq/L HCO3
– for every 10 mmHg PCO2
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?