Lec5 Oxygen Dissociation Curves of Haemoglobin PDF

# YOUR PATIENT A 70 year-old man presented to the Emergency Department following a house fire. Smoke rose through the floors and windows, and the patient was exposed to significant smoke inhalation. The man arrived at hospital drowsy and less responsive. Initial blood pressure was 139/84, pulse 74...

# YOUR PATIENT A 70 year-old man presented to the Emergency Department following a house fire. Smoke rose through the floors and windows, and the patient was exposed to significant smoke inhalation. The man arrived at hospital drowsy and less responsive. Initial blood pressure was 139/84, pulse 74 beats per minute. Arterial blood gas analysis showed pH 7.4, pO2 10.1 kiloPascal (NR > 10.6), and pCO2 of 5.46 kPa (NR 4.6-6.0) # LEARNING OBJECTIVES At the end of the lecture students will be able to: - Explain the biochemical basis of oxygen dissociation curve - Describe the Oxygen dissociation curve for Hemoglobin - Describe the Oxygen dissociation curve for Myoglobin - Describe the factors affecting binding of oxygen with hemoglobin - Describe the Allosteric Effectors of Oxygen dissociation curve - Explain transportation of oxygen and carbon dioxide through hemoglobin # OXYHEMOGLOBIN (oxyHb) = Hb with O₂ Its Relaxed From (R form) # DEOXYHEMOGLOBIN (deoxyHb) = Hb without O₂ Its Tense form (T form) # Hb binds Oxygen Cooperatively - The binding of first O2 molecule to one heme group increases the O2 affinity of the remaining heme groups in the same Hb tetramer. - It is more difficult for the first O2 to bind to Hb, the subsequent binding of O2 occurs with high affinity. - This is because the hemoglobin molecule changes its conformation (T to R), as oxygen binds. # Cooperative Oxygen Binding - It is more difficult for first oxygen molecule to bind to Hemoglobin subunit. - Steep upward curve shows that the subsequent binding of other oxygen occurs with high affinity. - The last oxygen is approximately 300 times greater than its affinity for first oxygen bound. # Oxygen Binding - It is more difficult for first oxygen molecule to `Hemoglobin subunit`. - Steep upward curve shows that the subsequent binding of other oxygen occurs with high affinity. - The last oxygen is approximately 300 times greater than its affinity for first oxygen bound. # Oxygen Binding Curve - Partial pressure of oxygen in lungs is 100 mm Hg while in tissues 40 mm Hg # Oxygen Dissociation Curve - Saturation of hemoglobin with oxygen at different partial pressures of oxygen is called "oxygen dissociation curve". - This graph shows that Myoglobin has higher oxygen affinity at all pO2 values than does hemoglobin. - P50 approx 1mm Hg for Mb - P50 approx 26mm Hg for Hb # Loading and Unloading Oxygen - The cooperative binding of O2 allows Hb to deliver more O2 to the tissues in response to relatively small changes in the partial pressure of O2. - In the lungs the partial pressure of O2 is high and Hb saturated (loaded) with O2. - In contrast in the peripheral tissues oxyHb releases (unloads) much of its O2 in the tissues. - If Hb behaved like Mb, very little oxygen would be released in capillaries of tissues. # Allosteric Property - Hb is a Allosteric protein - Hb has allosteric sites or regulatory sites to which effectors bind and control the oxygen binding properties of Hb. - Effectors either increase or decrease the affinity of Hb towards oxygen. # Allosteric Effects - The ability of Hb to reversibly bind oxygen is affected by the pO2, the pH of the environment, the pCO2 and availability of 2,3-bisphosphoglycerate. - These are collectively called allosteric effectors # Hemoglobin Positive Allosteric Effector - Oxygen Negative Allosteric Effectors - H+ (Bohr effect) - CO2 - 2,3-BPG # Allosteric Effectors - Effectors shift the ODC either to right or left. - A right shift indicates that the hemoglobin has low affinity for oxygen. - A left shift indicates that the hemoglobin has high affinity for oxygen. # Bohr Effect - The Bohr effect describes hemoglobin's lower affinity for oxygen if there is increased in the partial pressure of carbon dioxide and/or decreased blood pH. - This lower affinity, in turn, enhances the unloading of oxygen into tissues to meet the oxygen demand of the tissue - Therefore a shift to the right in the Oxygen Dissociation curve # Response to 2,3 BPG levels to Chronic Hypoxia and Anemia - An increase in 2,3-BPG concentration is found in most conditions in which the arterial blood is undersaturated with oxygen, as in congenital heart and chronic lung diseases, in most acquired anemias, at high altitudes, in alkalosis, and in hyperphosphataemia. - Chronic obstructive pulmonary disease (COPD) like emphysema. - Elevated 2,3-BPG levels lower the O2 affinity of Hb, permitting greater unloading of O2 in the capillaries of tissues # 2,3-Bisphosphoglycerate or 2,3-BPG - 2,3-Bisphosphoglycerate is an intermediate compound glycolysis. - Presence of 2,3-Bisphosphoglycerate significantly reduces the affinity of Hb for oxygen - Shifting the oxygen dissociation curve to the right # Response to 2,3 BPG levels to Chronic Hypoxia and Anemia - An increase in 2,3-BPG concentration is found in most conditions in which the arterial blood is undersaturated with oxygen, as in congenital heart and chronic lung diseases, in most acquired anemias, at high altitudes, in alkalosis, and in hyperphosphataemia. - Chronic obstructive pulmonary disease (COPD) like emphysema. - Elevated 2,3-BPG levels lower the O2 affinity of Hb, permitting greater unloading of O2 in the capillaries of tissues. # Carbaminohemoglobin - About 75% of tissue carbon dioxide is transported in bicarbonate form. - 5% is carried in simple solution and 15% is bound to the N-terminal amino groups of deoxygenated hemoglobin, forming Carbaminohemoglobin. # Effect of Temperature - Hyperthermia causes a rightward shift in the Oxygen Dissociation curve - While hypothermia causes a leftward shift. - Increasing temperature will weaken and denature the bond between an oxygen and a hemoglobin # Carboxy-Hb - The affinity of Hb for CO is 220 times greater than that for oxygen. - Carbon monoxide binds tightly but reversibly to the Hb iron forming carboxyhemoglobin (CO-Hb). # Carbon Monoxide (Competitive Inhibitor) - When CO binds to one or more of the four heme sites, Hb shifts to the R conformation causing the remaining heme sites to bind oxygen with high affinity - As a result affected Hb is unable to release oxygen in tissues. - Even minute concentrations of CO in the environment can produce toxic concentrations of carboxyhemoglobin in the blood. - From tobacco smoking, car exhaust and incomplete combustion in furnaces. - Treated with 100% O2 at high pressure. # SULF-HEMOGLOBIN - H₂S + Hb-O₂ → S-Hb + O₂ - Forms due to high sulfur levels in blood (irreversible reaction) - Reducing the capability of transporting oxygen. - This condition may occur from the chronic use of certain drugs. # MET-HEMOGLOBIN - The Fe⁺⁺ normally present in heme being replaced by Fe+++ - The ability to bind with an O₂ is lost. ODC shift towards right. - The normal erythrocyte contains small amount of met Hb, formed by spontaneous oxidation of Hb. # Met-hemoglobin - Met Hb is normally reconverted to Hb by reducing systems in the RBC, the most important of which is NADH Methemoglobin reductase. # Acquired (toxic) Methemoglobinemia - Usually arises following the ingestion of large amounts of drugs e.g. the sulphonamides, antimalaria drugs, excess of nitrites or certain oxidizing agents, present in the diet. - Superoxide anion, hydrogen peroxide and hydroxyl radical are free radicals. - Exposure to such substances in amounts that exceed the enzymatic reduction capacity of RBCs precipitates symptoms. # Congenital Methemoglobinemia - The most common cause of congenital methemoglobinemia is cytochrome b5 reductase deficiency # MET-HEMOGLOBIΝΕΜΙΑ HbM:- 1. Mutation in globin chain →HbM 2. ↓NADH Cytochrome b5 reductase (NADH methemoglobin reductase) SYMPTOMS - Chocolate cynosis (brownish-blue skin & membranes) - Chocolate colored blood. - Tissue hypoxia → anxiety, headache, dyspnea - Polycythemia. - Coma → death. # TREATMENT FOR METHEMOGLOBΙΝΕΜΙΑ - Exchange Transfusion - Hyperbaric Oxygen. - Methylene blue is the primary emergency treatment. 1-2 mg/kg as a 1% solution in IV saline over 3-5 minutes. - Methylene blue is oxidised → reduces Fe+3 →Fe+2