1	Control of Breathing N. Anaizi, PhD Associate Professor of Pharmacology & Physiology University of Rochester
2	Learning Objectives Describe the major components of the control system responsible for the regulation of respiration. Define acid-base balance. Describe the body’s main mechanisms for acid-base homeostasis. Describe the 4 primary acid-base disorders.
3	Objectives of Ventilation Provide enough O₂ for cell metabolism Remove the CO₂ produced in the course of cell metabolism. Also maintain pH within the normal range.
4	Basic Idea of Respiratory Control Maintain relatively constant the levels of:
5	Basic Elements of a Control System
6	Respiratory Control
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21	Acid-Base Balance N. Anaizi, PhD
22	Definitions and Basic Concepts An acid is a molecule or ion that tends to dissociate releasing protons (a base does the opposite). Strong acids dissociate completely and weak acids incompletely: HB Û H⁺ + B^- K = [H⁺][B^-] / [HB] [H⁺] = K[HB] / [B^-] - log [H⁺] = -log K - log [HB]/[B^-] pH = pK + log [B^-]/[HB]
23	Hederson-Hasselbalch Equation pH = 6.1 + log [HCO₃^-] / [CO₂]
24	[H⁺] in Body Fluids Is Extremely Low Compare: Na⁺ = 140 mmol/L K⁺ = 4 mmol/L H⁺ = 0.00004 mmol/L
25	Definitions and Basic Concepts Sorenson (1909): the “potential of H” pH = - Log [H⁺] = Log (1/ [H⁺]) Campbell (1962): [H⁺] in nanomoles/L One nanomole = 1 billionth of a mole
26	Why Must [H⁺] Be Maintained Within Certain Limits? The H⁺ atomic radius is extremely small (10^-15 meter) compared to other ions (Na⁺ = 10^-15 meter) Vital protein molecules (enzymes, receptors, hormones, etc.) are very sensitive D [H⁺]
27	Body Fluids Are Alkaline In pure water or neutral solutions: [H⁺] = [OH^-] = neutral In a neutral solution at 25°C: [H⁺] = [OH^-] = 100 nmol/L; pH = 7.00 In a neutral solution at 37°C: [H⁺] = [OH^-] = 216 nmol/L; pH = 6.65 Normally: [H⁺]_ECF = 40 and [H⁺]_ICF = 100 nM Therefore BFs are normally significantly alkaline relative to a neutral solution at body temperature. However, this alkalinity is being threatened ….
28	Endogenous Non-volatile Acid Production Highly dependent on diet. Average meat-eating human: 1 mEq/kg /day or 70,000,000 nmoles/day Sulfur-containing amino acids (methionine, cysteine, and cystine) yield sulfuric acid.: Methionine Þ glucose + urea + H₂SO₄ Organic phosphates yield phosphoric acid: 2H₂O + R₂-PO₄K Þ 2ROH + KH₂PO₄ Path. conditions: keto- and lactic acidoses; acidosis due ingestion of methanol, ethylene glycol, etc.
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30	What Makes A Good Buffer?
31	pKa = - log K The tendency of a weak acid (HB) to dissociate: HB Û H⁺ + B^- depends on the [H⁺] of the solution, and its K : K = [H⁺] [ B^- ] / [HB] The pK corresponds to the pH of the solution when the acid is 50% dissociated. Strong acids have low pK values, and weak acids have high pK values.
32	Biological Buffers Blood Buffers HCO₃^- / CO₂ Hemoglobin Proteins Phosphate
33	Acid-Base Balance
34	Attributes of the HCO₃^- / CO₂ Although its pKa is < ideal, it has unique properties: It is an open system Its acid component is actually a gas (CO₂) Its components are regulated relatively independently (kidney / lung) It is relatively abundant
35	What Happens to CO₂? In Tissues: CO₂ + H₂O Û H₂CO₃ Û H⁺ + HCO₃^-
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39	CO₂ Transport
40	Definitions Normally: [H⁺]_o = 40 and [H⁺]_i = 100 nmoles/L Acidemia: [H⁺]_o > 44 (pH < 7.36) Acidosis: a physiologic or pathophysiologic process that tends to cause acidemia. Alkalemia: [H⁺]_o < 36 ( pH > 7.44) Alkalosis: a physiologic or pathophysiologic process that tends to cause alkalemia.
41	What is an acid-base “disturbance”?
42	Primary Acid-Base Disturbances
43	The 4 Primary Acid Base Disorders Respiratory acidosis Main Problem: Ý arterial PCO2 Respiratory alkalosis Main Problem: ß arterial PCO2 Non-respiratory (metabolic) acidosis Main Problem: ß arterial [HCO₃^-] Non-respiratory (metabolic) alkalosis Main Problem: Ý arterial [HCO₃^-]
44	Secondary Response ... Aim of Secondary Response
45	Secondary Responses Respiratory acidosis Renal Response: Ý [HCO₃^-]_p Respiratory alkalosis Renal Response: ß [HCO₃^-]_p
46	Secondary Responses Non-respiratory (metabolic) acidosis Respiratory Response: ß P_aCO2 Non-respiratory (metabolic) alkalosis Respiratory Response: Ý P_aCO2
47	Predicted Secondary Responses Metabolic Acidosis P_CO2 falls 1.2 mm Hg per 1 mmol/L drop in [HCO₃^-] or P_CO2 = 1.5 [HCO₃^-] + 8 (P_CO2 = the last 2 digits of pH)
48	Predicted Secondary Responses Metabolic Alkalosis P_CO2 rises 0.7 mm Hg per 1 mmol/L rise in [HCO₃^-] P_CO2 = 0.9 [HCO₃^-] + 15
49	Predicted Secondary Responses Acute Respiratory Acidosis: [HCO₃^-] rises 0.12 mmol/L per mm Hg rise in P_CO2 Chronic Respiratory Acidosis: [HCO₃^-] rises 0.35 mmol/L per mm Hg rise in P_CO2 Acute Respiratory Alkalosis: [HCO₃^-] drops 0.2 mmol/L per mm Hg drop in P_CO2 Chronic Respiratory Alkalosis: [HCO₃^-] drops 0.4 mmol/L per mm Hg drop in P_CO2
50	Evaluating Acid-Base Disorders Conceptual Approach: PaCO₂, [HCO₃^-]_p, pH (or [H⁺]) Reference to data from whole-body titration studies. Singer & Hastings Method: PaCO₂, [HCO₃^-]_p, pH; and [Hb] or Hct “Whole-blood buffer base” (normal 48 mEq/L) Astrup & Siggaard-Andersen Method: PaCO₂ and pH Standard [HCO₃^-]_p and “Base Excess”
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56	Metabolic Acid-Base Disorders Show positive or negative Base Excess (BE) Base Excess = [HCO₃^-]_obs - [HCO₃^-]_pred [HCO₃^-]_obs = 0.03 PCO₂ x 10^{(pH- 6.1)} [HCO₃^-]_pred = 24 + (2.733 + 0.52 Hb)(7.4 - pH)
57	"Failure to dispose of the..." Failure to dispose of the usual acid load Renal failure; pRTA; RTA₄ Increased acid load Endogenous: lactic; ketoacidosis Exogenous: NH₄Cl, CaCl₂, Lysine HCl Ingestion (salicyl., methanol, e. glycol) Loss of HCO₃^- Via the GIT Via the Kidney
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59	"GI" GI H⁺Loss vomiting, NG suction, antacid therapy, etc. Renal H⁺ Loss loop or thiazide diuretics, excess mineralocorticoids, low Cl- intake, hypercalcemia & milk-alkali syndrome H⁺influx into the ICF hypokalemia
60	Identify These Disorders
61	Identify These Disorders