Physio 2 USMLE Flashcards
Tidal volume
Volume of air that enters and leaves the lung in a single cycle. 500ml
Functional residual capacity
Amount of air in the lungs after passive expiration. 2,700ml
Inspiratory capacity
Maximal volume of gas inspired from FRC. 4,000ml
Inspiratory reserve volume
Air that can be inhaled after normal inspiration. 3,500ml
Expiratory reserve volume
Air that can be expired after a normal expiration. 1,500ml
Residual volume
Air in the lungs after maximal expiration. 1,200ml
Vital capacity
Maximal air that can expired after maximal inspiration. 5,500ml
Total lung capacity
Air in the lungs after maximal inspiration. 6,700ml
Total ventilation
Total ventilation = Tidal volume X respiratory rate.
Dead space
Regions that contain air but do not exchange O2 and CO2
Anatomic dead space
Conducting zones. Approximately equal to person’t weight in pounds.
Alveolar dead space
Alveoli with air but without blood flow
Physiologic dead space
Anatomic dead space plus alveolar dead space
Alveolar ventilation
Tidal volume - anatomic dead space X respiratory rate.
Lung recoil
Force that collapses the lung. As the lung enlarges, recoil increases and vice versa.
Intrapleural pressure
Normally -5 cmH2O. Force that expands the lung. The more negative, the more lung expansion.
Lung mechanics before inspiration
Glotis is open but no air is flowing - alveolar pressure = 0. Intrapleural pressure and lung recoil are equal but opposite. Gravity increases intrapleural pressure at the apex and decreases it at the bases. Apex alveoli are more distended.
Lung mechanics during inspiration
Diaphragm contracts, intrapleural pressure becomes more negative. Expansion of alveoli makes alveolar pressure negative causing air to flow into the lungs.
Lung mechanics at the end of inspiration
Intrapleural pressure and recoil are the same but opposite. Alveolar pressure returns to zero and air stops flowing in.
Lung mechanics during expiration
Diaphragm relaxes, intrapleural pressure increases, lung recoil collpases the lung. Alveoli compress the air and alveolar pressure becomes positive and air flows out of the lungs until alveolar pressure is back to zero. Lung recoil and intrapleural pressure become equal but opposite.
Assisted control mode ventilation
Inspiration is initiated by the patient or the machine if no signal is detected.
Positive end-expiratory pressure
Does not allow intraalveolar pressure to return to zero at the end of expiration. The larger lung volume prevents atelectasis.
What is lung compliance?
It’s the change in volume with a change in pressure. Increased compliance means more air flows in with a given change in pressure. Decreased compliance means the opposite. The steeper the slope of the lung inflation curve, the greater the compliance. Emphysema = very compliant; fibrosis = not compliant.
Components of lung recoil
1) the tissue’s collagen and elastin fibers and 2) the surface tension (greatest component)
Functions of surfactant
Lowers lung recoil and increases compliance (↓ surface tension) more in small alveoli than large alveoli; reduces capillary filtration forces reducing tendency to develop edema.
Pathophysiology of respiratory distress syndrome
Low surfactant –> ↑ recoil, ↓ compliance (a greater change in intrapleural pressure is necessary to inflate the lungs); alveoli collapse (atelectasis); more negative intrapleural pressures promote capillary filtration (pulmonary edema)
Airway resistance
R = 1/r4; first and second bronchi have less radius than alveoli, therefore more resistance. Ach increases resistance (bronchoconstriction), catecholamines decrease resistance (bronchodilation)
Effect of lung volume on airway resistance
↑ lung volume –> ↑ radius –> ↓ resistance. The more negative the intrapleural pressure, the less resistance
Lung volumes in obstructive disease
↑ TLC, ↑ RV, ↑ FRC, ↓ FEV1, ↓ FVC, ↓ FEV1/FVC
Lung volumes in restrictive disease
↓ TLC, ↓ RV, ↓ FRC, ↓ FEV1, ↓ FEV, ↑ FEV1/FVC
Pressure of alveolar O2 and CO2
PAO2 = 100mmHg; PACO2 = 40mmHg
Pressure of venous pulmonary capillary O2 and CO2
PvO2 = 40mmHg; PvCO2 = 47mmHg
Pressure of arterial pulmonary capillary O2 and CO2
PO2 = 100mmHg; PCO2 = 40mmHg
Which factors affect PCO2?
Metabolic CO2 production and alveolar ventilation
Relationship between alveolar ventilation and PACO2
Inversely proportional. Hyperventilation decreases PACO2; hypoventilation increases PACO2.
Relationship between PAO2 and PACO2
↓ PACO2 –> ↑ PAO2 (hyperventilation); ↑ PACO2 –> ↓ PAO2 (hypoventilation)
Which factors affect PAO2?
Atmospheric pressure, oxygen concentration of inspired air and PACO2
What determines oxygen content?
Hemoglobin concentration. 1.34ml O2 combines with each gram of hemoglobin.
Amount of dissolved oxygen in the blood
0.3 volumes %; 0.3ml per 100ml of blood. Determines PO2 which acts to keep oxygen bound to Hb
What determines oxygen attachment to hemoglobin?
PO2 and the affinity of the individual attachment sites. The higher the affinity, the less PO2 is needed to keep it attached
What determines PO2?
Amount of oxygen dissolved in plasma. Normally 0.3 volumes %.
Site 4 of hemoglobin
Oxygen is attached at 100mmHg. Least affinity, last site to be saturated.
Site 3 of hemoglobin
Oxygen is attached at 40mmHg. More affinity than site 4, less affinity than site 2.
Site 2 of hemoglobin
Oxygen is attached at 26mmHg which is p50. More affinity, second site to be saturated.
Site 1 of hemoglobin
Oxygen remains attached under physiologic conditions. Highest affinity, first site to be saturated.
Factors that shift oxygen dissociation curve to the right
↑ CO2, ↑ 2,3BPG, fever, acidosis
Factors that shift oxygen dissociation curve to the left
↓ CO2, ↓ 2,3BPG, hypothermia, alkalosis, HbF, methemoglobin, carbon monoxide, stored blood
How is CO2 carried in the blood?
5% dissolved; 5% attached to Hb (carbamino compounds); 90% as bicarbonate.
Main drive for ventilation
H+ ions from dissociated H2CO3 which stimulate central chemoreceptors. H2CO3 is proportional to PCO2 of CSF
Central chemoreceptors
Sense [H+] which is proportional to PCO2 and H2CO3 of the CSF (not systemic)
Peripheral chemoreceptors
Carotid bodies (afferents via IX), aortic bodies (afferents via X). Monitor PO2 and [H+/CO2]
Main drive for ventilation in severe hypoxemia
Peripheral chemoreceptors sense PaO2 (dissolved oxygen) once PaO2 falls to 50-60mmHg.
Ventilatory response to chronic hypoventilation
Peripheral chemoreceptors are the main drive for ventilation eventhough PaCO2 is increased.
Ventilatory response to anemia
PaO2 and PACO2 are normal, therefore neither peripheral nor central chemoreceptors respond.
Central control of ventilation
Apneustic center in the caudal pons promotes prolonged inspiration. Pneumotaxic center in the rostral pons inhibits apneustic center. Efferents are from the medulla to the phrenic nerve (C1-C3) to the diaphragm
Differences in ventilation between the base and the apex of the lung
Base intrapleural pressure is -2.5, alveoli are compliant and small with a small volume of air but receive a large amount of ventilation; Apex pressure is -10, alveoli are large and stiff and contain a large volume of air but receive small amount of ventilation.
Differences in blood flow between the base and the apex of the lung
Blood vessels of the apex are less distended, have more resistance and receive less blood flow. Blood vessels of the base are more distended, have less resistance and receive more blood flow
Ventilation/perfussion relationship at the base of the lungs
Blood flow is higher than ventilation, the relationship is less than 0.8; the bases are underventilated, ↑ shunts
Ventilation/perfusion relationship at the apex of the lungs
Blood flow is lower than ventilation, the relationship is more than 0.8; the apex are overventilated, ↑ dead space
What does a ventilation/perfussion relationship under and over 0.8 mean?
Under 0.8 (at the bases) lungs are underventilated and less gas exchange takes place, therefore PACO2 and end-capillary PCO2 will be higher and PAO2 and end-capillary PO2 will be lower.
What is hypoxic vasoconstriction?
A decrease in PAO2 causes vasoconstriction and shunting of blood through that segment.
What is the effect of a thrombus in a pulmonary artery?
Blood flow decreases, therefore ↑ Va/Q –> ↓ PACO2, ↑ PAO2
What is the effect of a foreign object occluding a terminal bronchi?
Ventilation decreases, therefore ↓ Va/Q –> ↑ PACO2, ↓ PAO2
What constitutes a pulmonary shunt?
Regions of the lung where blood is not ventilated. Low Va/Q relationship.
What constitutes alveolar dead space?
Regions of the lung where there’s no blood flow in spite of ventilation. High Va/Q relantionship
Va/Q > 0.8
Represents alveolar dead space. Can be reversed with supplemental O2
Va/Q < 0.8
Represents a pulmonary shunt. Cannot be reversed with supplemental O2
What is the normal A-a gradient?
5-10 mmHg
Hypoventilation
↓ PAO2 but diffusion and A-a gradient are normal. Perfusion-limited defect.
What is a perfusion-limited defect?
There’s a lung problem but A-a gradient is normal
What is a diffusion-limited defect?
There’s a lung problem where A-a gradient is below normal, therefore diffusion isn’t normal
Diffusion impairment lung defect
Due to structural problem (↑ thickness or ↓ surface area). A-a gradient is more than normal. Supplemental oxygen compensates structural deficit but increased A-a gradient remains. Fibrosis, emphysema.
Diffusion capacity of the lung
Its measured with CO because it’s a diffusion-limited gas. Structural problems decrease CO uptake. It’s an index of surface area and membrane thickness.
Pulmonary right-left shunt
↓ Va/Q. There is an increased A-a gradient that is unresponsive to supplemental O2. Atelectasis or ARDS.
PO2 in atrial septal defect
↑ Right atrial PO2, ↑ right ventricular PO2, ↑ pulmonary artery PO2, ↑ pulmonary blood flow and pressure
PO2 in ventricular septal defect
No change in right atrial PO2, ↑ right ventricular PO2, ↑ pulmonary artery PO2, ↑ pulmonary flow and pressure
PO2 in patent ductus arteriosus
No change in right atrial PO2 nor right ventricular PO2, ↑ pulmonary artery PO2, ↑ pulmonary flow and pressure
Effect of sympathetic stimulation in the GI tract
↓ motility, ↓ secretions, ↑ contraction of sphincters
Effect of parasympathetic stimulation in GI tract
↑ motility, ↑ secretions, ↑ relaxation of sphincters (except LES which contracts), ↑ gastrin release
Hormones of the GI system
Gastrin, CCK, secretin, GIP
Stimulus for gastrin secretion
Stomach distension. Stomach acid in the duodenum inhibits gastrin release
Sources of gastrin
G cells of the stomach, antrum, duodenum
Actions of gastrin
Stimulates acid secretion by parietal cells, increases motility and secretions.
Source of secretin
S cells of the duodenum
Stimulus for secretin release
Acid entering the duodenum
Actions of secretin
Stimulates HCO3 secretion by pancreas to neutralize acid entering duodenum
Source of CCK
Cells lining the duodenum
Stimulus for CCK secretion
Fat and amino acids entering duodenum
Actions of CCK
Inhibits gastric emptying, stimulates pancreatic enzyme secretion, stimulates contraction of the gallbladder and relaxation of sphincter of Oddi.
Source of GIP
Duodenum
Stimulus for GIP secretion
Fat, carbs and amino acids
Actions of GIP
Inhibits stomach motility and secretion
Properties of GI smooth muscle
Stretch stimulates contraction, electrical syncytium with gap junctions, pacemaker activity
Factors that inhibit gastric motility
Acid in the duodenum (secretin), fat in the duodenum (CCK), hypoerosmolarity in duodenum, distension of duodenum
Factors that stimulate gastric motility
Distension of the stomach and ACh
What are the different contractions of the intestines?
Segmentation contractions (mixing), peristaltic movements (propulsive).
What factors control the ileocecal sphincter?
Distension of the ileum relaxes, distension of the colon contracts
What are the different contractions of the colon
Segmentation contractions (haustrations), peristalsis and mass movements
Composition of salivary secretions
Low in NaCl because of reabsorption; High in K and HCO3 because of secretion; alpha-amylase begins digestion of carbs; fluid is hypotonic due to NaCl reabsorption and impermeability of ducts to water
Parietal cells
Located in the middle part of the gastric glands. Secrete HCl and intrinsic factor.
Chief cells
Located in the deep part of the gastric glands. Secrete pepsinogen which is converted to pepsin by acid medium. Pepsin begins digestion of proteins to peptides
Mucous cells of the stomach
Located in the superficial part if the gastric glands (gastric pits). Secrete mucus and HCO3. Secreteion is stimulated by PGE2
Ionic composition of gastric secretions
High in H+, K+ and Cl-, low in Na+. Vomiting produces metabolic alkalosis and hypokalemia.
Control of acid secretion
Acetylcholine, histamine and gastrin stimulate parietal cells to secrete acid.
Secretion of acid by parietal cells
CO2 is extracted from the blood and combined into H2CO3 by carbonic anhydrase. H+ ions are exchanged by the proton pump for K+ ions (active antitransport)
Pancreatic amylase
Hydrolyzes α-1,4-glucoside bonds forming α-limit dextrins, maltotriose and maltose
Pancreatic lipase
Needs colipase which displaces bile from surface of micelles. Lipase digests triglycerides to two free fatty acids and one 2-monoglyceride
Cholesterol esterase
Hydrolizes cholesterol esters to yield cholesterol and free fatty acids
Pancreatic proteases
Trypsinogen is converted to trypsin by enterokinase –> chymotrypsinogen is converted to chymotrypsin by trypsin –> procarboxypeptidase is converted to carboxypeptidase by trypsin
Ionic composition of pancreatic secretions
Isotonic due to permeability of ducts to water and high in HCO3. Stimulated by CCK and secretin.
What are the primary bile acids?
Cholic acid and chenodeoxycolic acid. Synthesized in the liver from cholesterol.
How are bile salts formed?
Bile acids (cholic and deoxycholic) are conjugated with glycine and taurine which mix with cations to form salts.
What are the secondary bile acids?
Formed by deconjugation of bile salts by enteric bacteria - deoxycholic acid (from cholic acid) and lithocolic acid (from chenodeoxycholic acid). Lithocholic acid is hepatotoxic and is excreted.
Enterohepatic circulation
Bile acids are reabsorbed only in the distal ileum. Resection or malabsoption syndromes lead to steatorrhea and cholesterol gallstones.
What are the components of bile?
Conjugated bile acids (cholic and chenodeoxycholic), billirubin, lecithin and cholesterol.
How are carbohydrates absorbed?
Glucose and galactose via active secondary Na cotransporter. Fructose is absorbed independently
How are amino acids absorbed?
Secondary active transport linked to Na and receptor-mediated endocytosis.
How are lipids absorbed?
Micelles diffuse to the brush border then digested lipids (2-monoglycerides, fatty acids, cholesterol and ADEK vitamins) diffuse into enterocytes. Triglycerides are resynthesized and packaged as chylomicrons with apoB48. Leave the intestine via lymphatics to thoracic duct.
↑ glomerular pressure, ↓ peritulbuar pressure, ↓ RPF
Efferent arteriole constriction
↓ glomerular pressure, ↑ peritubular pressure, ↑ RPF
Efferent arteriole dilation
↓ glomerular pressure, ↓ peritulbuar pressure, ↓ RPF
Afferent arteriole constriction
↑ glomerular pressure, ↑ peritulbuar pressure, ↑ RPF
Afferent arteriole dilation
Afferent arteriole dilation
↑ glomerular pressure, ↑ peritulbuar pressure, ↑ RPF, ↑ GFR
Afferent arteriole constriction
↓ glomerular pressure, ↓ peritulbuar pressure, ↓ RPF, ↓ GFR
Efferent arteriole dilation
↓ glomerular pressure, ↑ peritubular pressure, ↑ RPF, ↓ GFR
Efferent arteriole constriction
↑ glomerular pressure, ↓ peritulbuar pressure, ↓ RPF, ↑ GFR, ↑ FF
Plasma oncotic pressure changes as blood flows through the nephron
Oncotic pressure increases because filtered fluid increases protein concentration. Oncotic pressure is resposible for peritubular reabsorption
Normal capillary hydrostatic pressure of the glomerulus
45 mmHg
Normal capillary oncotic pressure of the glomerulus
27 mmHg
Normal hydrostatic pressure of bowman’s capsule
10 mmHg
Normal GFR value
120 ml/min
Normal RPF value
600 ml/min
Normal filtration fraction value
FF = GFR/RPF = 120mi/min / 600ml/min = 0.20
Effect of sympathetic stimulation in the nephron
↓ GFR, ↑ FF, ↑ peritubular reabsoption
Effect of angiotensin II in the kidney
Vasoconstriction of the efferent arteriole more than afferent –> maintains GFR
Filtered load
Rate at which a substance filters into Bowman’s capsule = FL = GFR x Free plasma concentration
Excretion of a substance in the urine
Excretion = filtered load + (amount secreted - amount reabsorbed) = filtered load + transport OR urine concentration X urine flow rate
Characteristics of a Tm system
Carriers become saturated, carriers have high affinity, low back leak. The filtered load is reabsorbed until carriers are saturated - the excess is excreted.
Renal treshold for glucose
180 mg/dl or 1.8 mg/ml. Represents the beginning of splay.
Tm rate of reabsorption of glucose
375 mg/min. Represents the maximum filtered load that can be reabsorbed when all carriers in the kidney are saturated (end of splay region).
Glucose reabsorption graph
At normal glucose levels, the amount filtered is the same as the amount reabsorbed. At treshold (beginning of splay), the excretion curve starts to ascend and the amount filtered exceeds the amount reabsorbed.
Substances that are reabsorbed using a Tm system
Glucose, amino acids, small peptides, myoglobin, ketones, calcium, phosphate.
Characteristics of a gradient-time system
Carriers are not saturated, carriers have low affinity, high back leak
Substances that are reabsorbed using a gradient-time system
Sodium, potassium, chloride and water
Substances secreted using a Tm system
PAH. 20% filtered, 80% secreted.
Graph for PAH secretion
At low plasma concentration secretion is 4 times the filtered load. When carriers become saturated, secretion reaches a plateau and the amount excreted is proportional to the amount filtered.
How is the net transport rate for a substance calculated?
Net transport rate = filtered load - excretion rate = (GFR X Px) - (Ux X V)
Effects of blood pressure changes in the kidney
GFR and RBF are maintained constant within the autoregulatory range. Urine flow is directly proportional to blood pressure due to pressure natriuresis and pressure diuresis.
What is clearance and how is it calculated?
It’s the volume of plasma cleared of a substance over time. Clearance = excretion / Px = Ux X V / Px
Characteristics of glucose clearance
At normal glucose levels, clearance is zero. Above treshold levels, clearance increases as plasma concentration increases but never reaches GFR as there’s always glucose reabsorption.
Characteristics of inulin clearance
A constant amount of inulin is cleared regardless of plasma concentration (parallel line to x axis). Inulin clearance is equal to GFR because it’s not secreted nor reabsorbed. If GFR increases, clearance increases (line shifts upward), and vice versa.
Characteristics of creatinine clearance
A constant amount of creatinine is cleared regardless of plasma concentration, but creatinine clearance is more than GFR because some is always secreted.
Characterisics of PAH clearance
As plasma concentration increases, clearance decreases because carriers that mediate active secretion become saturated. At normal levels, PAH clearance = RPF because all is excreted.
How is GFR calculated using inulin?
GFR is equal to inulin clearance because it’s only filtered and none is secreted nor reabsorbed. Cin = GFR = Uin X V / Pin
How is creatinine production calculated?
Creatinine production = creatinine excretion = filtered load of creatinine = [Cr]p X GFR. Creatinine is filtered and secreted, not reabsorbed.
How does inulin concentration change as it passes through the nephron?
Inulin becomes more concentrated as it passes through the tubules because water is being reabsorbed and not inulin.
Gold standard to measure GFR
Inulin clearance because it’s filtered but not secreted nor reabsorbed.
Gold standard to measure RPF
PAH clearance because some is filtered and the remaining is all secreted.
How is effective RPF calculated?
PAH clearance = RPF = Upah X V / Ppah
How is renal blood flow calculated?
ERPF / 1-Hct; ERPF = Upah X V / Ppah
What does positive free water clearance mean?
Water is being eliminated. Hypotonic urine is being formed to increase plasma osmolarity.
What does negative free water clearance mean?
Water is being conserved. Hypertonic urine is being formed to lower plasma osmolarity.
How is free water clearance calculated?
V - (Uosm(V) / Posm)
Which substance is cleared the most: PAH, inulin, glucose, creatinine
PAH
Which substances are cleared more than glucose?
Sodium, inulin, creatinine, PAH
Which substance is cleared the least: PAH, inulin, glucose, creatinine
Glucose
Which substances are cleared more than inulin?
Creatinine, PAH
Which substances are cleared less than creatinine?
Inulin, glucose, sodium
Transporters in the luminal membrane of the proximal tubule
Secondary Na/glucose cotransporter, secondary Na/amino acid cotransporter, secondary Na/H countertransporter
What substances are reabsorbed in the proximal tubule and how much?
Na (2/3 of filtered load), glucose (100%), amino acids (100%), HCO3 (indirectly, 80%), H20 (2/3), K (2/3), Cl (2/3)
Tubular osmolarity at beginning and end of proximal tubule
At the beginning and end is isotonic with plasma but only 1/3 of the filtered load.
Transporters in the basal membrane of proximal tubule
Na/K ATPase - luminal membrane secondary Na transporters depend on this.
Transporters in the basolateral membrane of proximal tubule
Na/K ATPase - luminal membrane secondary Na transporters depend on this.
Most energy-dependant process in the nephron
Active reabsorption of Na by the basal and basolateral Na/K ATPase
Characteristics of the loop of henle
Descending limb is permeable to water so water difuses out and intraluminal osmolarity increases to 1,200mOsm Ascending limb is impermeable to water and Na is actively pumped out by Na/K/2Cl pump so fluid becomes hypotonic. Flow is slow, anything that increases flow, decreases capacity to concentrate urine.
Characteristics of the collecting duct
Impermeable to water unless ADH is present. ADH increases permeability to H20 and urea to concentrate urine. Tight junctions with little back-leak.
Specialized cells of the distal tubule and collecting duct
Principal cells (aldosterone) and intercalated cells (create HCO3)
Actions of principal cells of the distal tubule and collecting duct
Aldosterone increases Na receptors in the membrane and increases primary transport by Na/K ATPase. Secondary transport of Na and secretion of K.
Actions of the distal tubule and collecting duct
Reabsorption of Na and secretion of K (stimulated by aldosterone), acidification of the urine (secretion of H and creation of HCO3)
Urine buffer systems
H2PO4- (dihydrogen phosphate) (tritratable acid) buffers 33% of secreted H. NH4+ (amonium) (nontritratable acid) buffers the remaining secreted H.
How is potassium affected by acidosis?
High concentration of ECF H –> H diffuses to ICF –> K diffuses to ECF –> hyperkalemia
How is potassium affected by alkalosis?
Low concentration of ECF H –> H diffuses to ECF –> K diffuses to ICF –> hypokalemia
Potassium dynamics in acute alkalosis
Hypokalemia, ↑ intracellular K, ↑ renal K excretion, negative K balance
Potassium dynamics in chronic alkalosis
Hypokalemia, ↓ intracellular K, ↑ renal K excretion, negative K balance
Potassium dynamics in acute acidosis
Hyperkalemia, ↓ intracellular K, ↓ renal K excretion, positive K balance
Potassium dynamics in chronic acidosis
Hyperkalemia, ↓ intracellular K, ↑ renal K excretion, negative K balance
How is potassium balance in acute acidosis?
Positive (potassium is reabsorbed)
How is potassium balance in acute alkalosis?
Negative (potassium is excreted)
How is potassium balance in chronic alkalosis?
Negative (potassium is excreted)
How is potassium balance in chronic acidosis?
Negative (potassium is excreted)
How is plasma potassium concentration in alkalosis?
Hypokalemia
How is plasma potassium concentration in acidosis?
Hyperkalemia
What is the difference in potassium dynamics between acute and chronic alkalosis?
Acute alkalosis –> ↑ intracellular K; Chronic alkalosis –> ↓ intrecellular K
What is the difference in potassium dynamics between acute and chronic acidosis?
Acute acidosis –> ↓ renal K excretion, positive K balance; Chronic acidosis –> ↑ renal K excretion, negative K balance
Changes in respiratory acidosis
Hypoventilation –> ↑ PaCO2 –> ↑ H and slight ↑ in HCO3 –> ↓ pH
Changes in respiratory alkalosis
Hyperventilation –> ↓ PaCO2 –> ↓ H and HCO3 –> ↑ pH
Changes in metabolic acidosis
Gain of H or loss of HCO3 –> ↓ HCO3 –> ↑ pH. To see if gain of H or loss of HCO3 check anion gap.
Changes in metabolic alkalosis
Loss of H or gain in HCO3 –> ↑ HCO3 –> ↑ pH. To see if gain of H or loss of HCO3 check anion gap.
Normal values of PCO2, HCO3 and pH
pH = 7.4; PCO2 = 40mmHg; HCO3 = 24mmol/L
↑pH, ↑ HCO3, ↑PCO2, ↓PO2, alkaline urine
Partially compensated metabolic alkalosis
↓pH, ↑PCO2, ↑HCO3, ↓PO2, acid urine
Partially compensated respiratory acidosis
↑pH, ↓PCO2, ↓HCO3, normal PO2, alkaline urine
Partially compensated respiratory alkalosis
↓pH, ↓PCO2, ↓HCO3, normal PO2, acid urine
Partially compensated metabolic acidosis
Normal plasma anion gap value
PAG = 12
Conditions that increase plasma anion gap
Lactic acidosis, ketoacidosis, ingestion of salicylate
Hyperchloremic non-anion gap metabolic acidosis
Loss of HCO3 (as in diarrhea) causes increased absorption of solutes and water, increasing Cl. Therefore ↓HCO3 and ↑Cl with a plasma anion gap of 12.
Factors that affect hormone binding protein synthesis
Estrogen increases binding proteins; androgens decrease binding proteins. In pregnancy there’s increased total hormones with normal levels of free hormone.
Site of synthesis of CRH
Paraventricular nucleus
Site of synthesis of TRH
Paraventricular nucleus
Site of synthesis of PIF
Arcuate nucleus
Site of synthesis of GHRH
Arcuate nucleus
Site of synthesis of GnRH
Preoptic region
Site of synthesis of ADH
Supraoptic and paraventricular nuclei
How do hypothalamic hormones reach the anterior pituitary?
Hormones are released in the hypophyseal-portal system
Hypothalamic hormones
GHRH, GnRH, PIF (dopamine), TRH, CRH, Somatostatin, ADH, prolactin
Anterior pituitary hormones
ACTH, TSH, LH, FSH, GH, prolactin
Sheehan syndrome
Ischemic necrosis of the pituitary due to severe blood loss during delivery. Causes hypopituitarism.
Obstruction of pituitary stalk
Adenoma compresses pituitary stalk and decreases secretion of anterior pituitary hormones except prolactin.
What prevents downregulation of pituitary receptors?
Pulsatile release of hypothalamic hormones.
Hyperprolactinemia
Results from dopamine antagonists or pituitary adenomas that compress the pituitary stalk. Amenorrhea, galactorrhea, decreased libido, impotence, hypogonadism
What hormone controls release of cortisol and adrenal androgens?
ACTH
What hormone regulates release of aldosterone?
Angiotensin II and also potassium in hyperkalemia
Layers of the adrenal cortex
From external to internal: glomerulosa (aldosterone), fasciculata (cortisol), reticularis (androgens). “Salt, Sugar and Sex; the deeper it goes the sweeter it gets”
Consequences of loss of zona glomerulosa
No aldosterone: loss of Na, ↓ECF, ↓blood pressure, circulatory shock, death
Consequences of loss of zona reticularis
No cortisol: circulatory failure (cortisol is permissive for cathecolamine vasoconstriction), can’t mobilize energy stores during exercise of cold (hypoglycemia)
Consequences of loss of adrenal medulla
No epinephrine: decreased capacity to mobilize fat and glycogen during stress. Not necessary for survival.
What are the 17-OH steroids?
17OHpregnenolone, 17OHprogesterone, 11-deoxycortisol, cortisol. Urinary 17OH steroids are an index of cortisol secretion.
What is the rate-limiting enzyme for steroid hormone synthesis?
Desmolase - converts cholesterol into pregnenolone
What are the 17-ketosteroids?
DHEA and androstenidione
DHEA
Weak androgen 17-ketosteroid conjugated with sulfate to make it water-soluble
What is measured as an index of androgen production?
Urinary 17-ketosteroids. In females and prepubertal males is an index of adrenal 17-ketosteroids. In postpubertal males is an index of 2/3 adrenal androgens and 1/3 testicular androgens.
Stimulus for the zona glomerulosa
Angiotensin II and potassium in hypekalemia stimulate production of aldosterone
Hormone responsible for negative feedback for ACTH release
Cortisol
Enzyme deficiencies that produce congenital adrenal hyperplasia and low cortisol levels
21β-OH, 11β-OH and 17α-OH all result in low cortisol levels.
21β-OH deficiency
No aldosterone: loss of Na, ↓ECF, ↓blood pressure in spite of high renin and angiotensin II, circulatory shock, death. No cortisol (low 17OH steroids): skin hyperpigmentation (due to excess ACTH), adrenal hyperplasia, hypotension (persmissive for catecholamines), fasting hypoglycemia. Excess androgens (17-ketosteroids): female pseudohermaphrodite, hirsutism
11β-OH deficiency
Excess 11-deoxycorticosterone: Na and water retention, low-renin hypertension. No cortisol (low 17OH steroids): skin hyperpigmentation (due to excess ACTH), adrenal hyperplasia, fasting hypoglycemia. Excess androgens (17-ketosteroids): female pseudohermaphrodite, hirsutism
17α-OH deficiency
Excess 11-deoxycorticosterone and low aldosterone (no AII): Na and water retention, low-renin hypertension. No cortisol: skin hyperpigmentation (due to excess ACTH), adrenal hyperplasia; corticosterone partially compensates low cortisol levels. No 17-ketosteroids: male pseudohermaphrodite, no testosterone, no estrogen.
↓17OH-steroids ↑ACTH, ↓blood pressure, ↓mineralocorticoids, ↑17-ketosteroids
21β-OH deficiency
↓17OH-steroids ↑ACTH, ↑blood pressure, ↓aldosterone, ↑11-deoxycorticosterone, ↑17-ketosteroids
11β-OH deficiency
↓17OH-steroids ↑ACTH, ↑blood pressure, ↑ aldosterone, ↑11-deoxycorticosterone, ↓17-ketosteroids
17α-OH deficiency
Stress hormones
GH, Glucagon, cortisol, epinephrine
Actions of GH in stress situations
Mobilizes fatty acids by increasing lipolysis in adipose tissue
Actions of glucagon in stress situations
Mobilizes glucose by increasing liver glycogenolysis
Actions of cortisol in stress situations
Mobilizes fat, carbs and proteins
Actions of epinephrine in stress
Mobilizes glucose via glycogenolysis and fat via lipolysis.
Metabolic actions of cortisol
1) Protein catabolism and delivery of amino acids; 2) lipolysis and delivery ofr fatty acids and glycerol 3) gluconeogenesis raises glycemia; also inhibits glucose uptake.
Permissive actions of cortisol
Enhances glucagon (without cortisol –> fasting hypoglycemia); enhances epinephrine (without cortisol –>hypotension)
α-MSH
Stimulates melanocytes and causes darkening of skin. Synthesized along with ACTH from pro-opiomelanocortin.
↑cortisol, ↓CRH, ↓ACTH, no hyperpigmentation
Primary hypercortisolism
↓cortisol, ↑CRH, ↑ACTH, hyperpigmentation
Addison disease - primary hypocortisolism
↑cortisol, ↓CRH, ↑ACTH, hyperpigmentation
Secondary hypercortisolism
↓cortisol, ↑CRH, ↓ACTH, no hyperpigmentation
Secondary hypocortisolism
↓cortisol, ↓CRH, ↓ACTH, no hyperpigmentation, symptoms of excess cortisol
Steroid administration
Cushing syndrome
Protein depletion, weak inflammatory response, poor wound healing, hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, osteoporosis, purple striae, hirsutism, hypertension, hypokalemic alkalosis, buffalo hump
Actions of aldosterone
↑Na channels in lumen of principal cells, ↑activity of Na/K ATPase of principal cells –> increases Na reabsorption. Also ↑ secretion of K and H leading to hypokalemic metabolic alkalosis.
Addison disease
↑ ACTH, hyperpigmentation, hypotension (no aldosterone, no cortisol), hyperkalemic metabolic acidosis (no aldosterone), loss of body hair (no androgens), hypoglycemia, ↑ ADH secretion
Causes of secondary hyperaldosteronism
CHF, vena cava constriction, cirrhosis, renal artery stenosis
Primary hyperaldosteronism
Na and water retention, hypertension, hypokalemic metabolic alkalosis, ↓ renin and angiotensin, no edema due to pressure diuresis and natriuresis.
Primary hypoaldosteronism
Na and water loss, hypotension, hyperkalemic metabolic acidosis, ↑ renin and angiotensin II, no edema
Secondary hyperaldosteronism
↑ renin and angiotensin II, ↑ Na and water retention in venous circulation, edema
Factors that influence ADH secretion
↑ osmolarity –> ↑ ADH secretion; ↓ blood volume –> baroreceptors –> medulla –> ↑ ADH secretion
Actions of ADH
Inserts water channels in luminal membrane of collecting ducts, increases reabsorption of water.
Central diabetes insipidus
Not enough ADH secreted. Dilute urine is formed in spite of water deprivation. Responds to injected ADH.
Nephrogenic diabetes insipidus
ADH is secreted but ducts are unresponsive to it. Dilute urine is formed in spite of water deprivation or injected ADH.
SIADH
Excessive secretion of ADH in spite of low osmolarity. Concentrated urine is formed.
↓ permeability of collecting ducts, ↑ urine, ↓ urine osmolarity, ↓ ECF, ↑ osmolarity
Diabetes insipidus
↑ permeability of collecting ducts, ↓ urine, ↑ urine osmolarity, ↓ ECF, ↑ osmolarity
Dehydration
↑ permeability of collecting ducts, ↓ urine, ↑ urine osmolarity, ↑ ECF, ↓ osmolarity
SIADH
↓ permeability of collecting ducts, ↑ urine, ↓ urine osmolarity, ↑ ECF, ↓ osmolarity
Primary polydipsia
Actions of ANP
Atrial stretch or ↑ osmolarity –> ANP secretion –> dilation of afferent, constriction of efferent –> ↑ GFR –> natriuresis; also decreases permeability of collecting ducts to water.
Delta cells of the pancreas
Between alpha and beta cells, represent 5% of islets. Secrete somatostatin.
Alpha cells of the pancreas
Near the periphery of the islets, represent 20%. Secrete glucagon.
Beta cells of the pancreas
In the center of the islets, represent 60-75%. Secrete insulin and C peptide.
Insulin receptor
Has intrinsic tyrosine kinase activity. Insulin receptor substrate binds tyrosine kinase, activates SH2 domain proteins: PI-3 kinase (translocation of GLUT-4), p21RAS.
Tissues that require insulin for glucose uptake
Resting skeletal muscle and adipose tissue
Tissues independent of insulin for glucose uptake
Brain, kidneys, intestinal mucosa, red blood cells, beta cells of the pancreas.
Anabolic hormones
Insulin, GH/IGF-1, androgens, T3/T4, IGF-1 (somatomedin C)
Effects of insulin on potassium
Increases Na/K ATPase uptake of K. Insulin + glucose used to treat hyperkalemia.
Mechanism of insulin release
Glucose enters β cells and is metabolized –> ↑ ATP –> closes K channels –> ↑ depolarization –> ↑ Ca influx –> exocytosis of insulin.
Factors that stimulate secretion of insulin
Glucose, arginine, GIP, glucagon
Factors that inhibit insulin release
Somatostatin, norepinephrine via α1 receptors
↑ glucose, ↑ insulin, ↑ C peptide
Type 2 diabetes
↑ glucose, ↓ insulin, ↓ C peptide
Type 1 diabetes
↓ glucose, ↑ insulin, ↑ C peptide
Insulinoma
↓ glucose, ↑ insulin, ↓ C peptide
Factitious hypoglycemia (insulin injection)
Actions of somatomedin C
Increases cartilage synthesis at epiphyseal plates (↑ bone length). Also ↑ lean body mass. Protein-bound and long half-life correlates to GH secretion. Also called IGF-1.
Secretion of GH
Pulsatile during non-REM sleep; more frequent in puberty due to increased androgens; requires thyroid hormones; decreases in the elderly.
Factors that stimulate GH secretion
Deep sleep, hypoglycemia, exercise, arginine, GHRH, low somatostatin
Factors that inhibit GH secretion
Negative feedback by GH on GHRH; positive feedback on somatostatin by IGF-1
Dwarfism
Due to GH insensitivity during prepuberty
Acromegaly
Due to excess GH in postpuberty. Enlargement of hands, feet and lower jaw, increased proteins, decreased fat, visceromegaly, cardiac insuficiency.
Composition of bone
Phosphate and calcium precipitate forming hydroxyapatite in osteoid matrix.
Actions of PTH
Rapid actions: increases Ca reabsorption in distal tubules and decreases phosphate reabsorption in proximal tubules, thus lowering blood phosphate and lowering solubility product which leads to bone resorption and raises plasma Ca. Slow actions: increases number and activity of osteoclasts (via osteoclast activating factor released by osteoblasts), increases activity of alpha-1 hydroxylase in the proximal tubules which increases active vitamin D and absorption of Ca and phosphate in the instetines.
Clinical features of primary hyperparathyroidism
↑ plasma Ca and ↓ plasma phosphate, phosphaturia, polyuria, calciuria (filtered load of Ca exceeds Tm), ↑ serum alkaline phosphatase, ↑ urinary hydroxyproline, muscle weakness, easy fatigability.
Clinical features of primary hypoparathyroidism
↓ plasma Ca and ↑ plasma phosphate, hypocalcemic tetany due to increased excitability of motor neurons.
↑ PTH, ↑ Ca, ↓ phosphate
Primary hyperparathyroidism. Causes: parathyroid adenoma (MEN I and II), ectopic PTH tumor (lung squamous CA)
↓ PTH, ↓ Ca, ↑ phosphate
Primary hypoparathyroidism. Cause: surgical removal of parathyroid.
↑ PTH, ↓ Ca, ↑ phosphate
Secondary hypoparathyroidism due to renal failure (no active vitamin D, decreased GFR)
↑ PTH, ↓ Ca, ↓ phosphate
Secondary hyperparathyroidism. Causes: deficiency of vitamin D due to bad diet or fat malabsorption.
↓ PTH, ↑ Ca, ↑ phosphate
Secondary hypoparathyroidism due to excess vitamin D.
Vitamin D synthesis
Dietary and skin cholecalciferol is hydroxylated by 25-hydroxylase in the liver and activated to 1,25 di-OH cholecalciferol by 1-alpha hydroxylase in the proximal tubules.
Actions of 1,25 di-OH cholecalciferol
Increases Ca binding proteins by intestinal cells which increases intestinal reabsorption of Ca and phosphate. Also increases reabsorption of Ca in the distal tubules. Increased serum Ca promotes bone deposition.
Osteomalacia
Underminerilized bone in adults due to vitamin D deficiency leads to bone deformation and fractures. Low calcium leads to secondary hyperparathyroidism.
Rickets
Underminerilized bone in children due to vitamin D deficiency leads to bone deformation and fractures. Low calcium leads to secondary hyperparathyroidism.
Excess vitamin D
Leads to bone reosprtion and demineralization
Synthesis of thyroid hormones
1) Iodine is actively transported into follicle cell; 2) thyroglobulin is synthesized in the RER, glycosylated in the SER and packaged in the GA; 3) Peroxidase is found in the luminal membrane and catalizes oxidation of I-, iodination of thyroglobulin and coupling to form MITs and DITs; 4) iodinated thyroglobulin is stored in the follicle lumen.
Structure of thyroid hormones
T4 has iodine attached to carbons 3 and 5 of both fenol rings; T3 has iodide attached to carbons 3 and 5 of the amino terminal fenol ring and the 3 prime carbon of the hydroxyl end fenol ring; reverse T3 has iodide in carbon 3 of the amino terminal fenol ring but not carbon 5.
Secretion of thyroid hormones
Iodinated thyroglobulin is endocytosed from the lumen of the follicles into lysosomes. Thyroglobulin is degraded into amino acids, T3, T4, DITs and MITs. T4 and T3 are secreted in a 20:1 ratio. DITs and MITs are deiodinated and iodine is recycled.
Transport of thyroid hormones
99% is bound to TBG, 1% is free. T4 has greater affinity for TBG and a half-life of 6 days. T3 has greater affinity for nuclear receptor and is the active form with a 1 day half-life. 50:1 T4/T3 ratio in periphery.
Activation and degradation of thyroid hormones
5’ monodeiodinase activates T4 into T3. 5-monodeiodinase inactivates T4 into reverse T3.
Actions of thyroid hormones
↑ metabolic rate by ↑ Na/K ATPase except in brain, uterus and testes; essential for brain maturation and menstrual cycle; permissive for bone growth; permissive for GH synthesis and secretion; ↑ clearance of cholesterol; required for activation of carotene; ↑ intestinal glucose absorption; ↑ affinity and number of β1 receptros in the heart.
Effects of hypothyroidism in newborns
↓ dendritic branching and myelination lead to mental retardation.
Effects of hypothyroidism in juveniles
Cretinism results in ↓ bone growth and ossification –> dwarfism. Due to lack of permissive action on GH.
Control of thyroid hormone secretion
Circulating T4 is responsible for negative feedback of TSH by decreasing sensitivity to TRH. T4 is converted to T3 in the thyrotroph to induce negative feedback.
Effects of TSH
Rapid actions: ↑ iodide trapping, ↑ synthesis of thyroglobulin, ↑ reuptake of iodinated thyroglobulin, ↑ secretion of T4; late effects: ↑ blood flow to thyroid gland, ↑ hypertrophy of follicles and goiter.
↓ T4, ↑ TSH, ↑ TRH
Primary hypothyroidism; ↑ TSH is the more sensible index
↓ T4, ↓ TSH, ↑ TRH
Pituitary (secondary) hypothyroidism
↓ T4, ↓ TSH, ↓ TRH
Hypothalamic (tertiary) hypothyroidism
↑ T4, ↑ TSH, ↓ TRH
Pituitary (secondary) hyperthyroidism
↑ T4, ↓ TSH, ↓ TRH
Graves disease
Pathophysiology of iodine deficiency
Thyroid makes less T4 and more T3 so actions of T3 may be normal but low levels of T4 stimulate TSH secretion with development of goiter. Thus euthyroid with goiter.
Clinical features of hypothyroidism
↓ basal metabolic rate with cold intolerance, ↓ cognition, hyperlipidemia, nonpitting myxedema (mucopolysacchride accumulation around eyes retains water), physiologic jaundice (↑ carotene), hoarse voice, constipation, anemia, lethargy
Clinical features of hyperthyroidism
↑ metabolic rate with heat intolerance and sweating, ↑ apetite with weight loss, muscle weakness, tremor, irritability, tachycardia, exophthalmos.
Leydig cells
Stimulated by LH; produce testosterone for peripheral tissues and Sertoli cells. Testosterone provides negative feedback for LH secretion by pituitary.
Sertoli cells
Stimulated by FSH; produce inhibins (inhibits secretion of FSH), estradiol (testosterone is converted by aromatase), androgen binding proteins and growth factors for sperm. Responsible for development of sperm in males. Also MIH in male fetus.
↓ sex steroids, ↑ LH, ↑ FSH
Primary hypogonadism or postmenopause.
↓ sex steroids, ↓ LH, ↓ FSH
Pituitary hypogonadism or constant GnRH infusion (downregulates GnRH receptors of pituitary.
↑ sex steroids, ↓ LH, ↓ FSH
Anabolic steroid therapy. LH supression causes Leydig cell atrophy with decreased Leydig testosterone which suppresses spermatogenesis.
↑ sex steroids, ↑ LH, ↑ FSH
Pulsatile infusion of GnRH
Fetal development of male structures
LH –> Leydig cells –> testosterone –> Wolffian ducts (internal male structures: epididymis, vasa deferentia ans seminal vesicles). Testosterone + 5-alpha reductase –> dihydrotestosterone –> urogenital sinus and external organs. MIH by Sertoli cells –> regression of Mullerian ducts and female structures.
