Murmurs

A 23-year-old intravenous heroin user is brought to the emergency department by ambulance after being found unresponsive. The patient is resuscitated with naloxone and is admitted to the hospital, where he has a fever of 39°C (102.2°F). Upon examination, a "blowing" systolic heart murmur is heard best at the lower sternal border. The murmur varies with respiration, becoming louder with inspiration. Additionally, the examiner notes a prominent jugular venous pulse.

Which of the following valve abnormalities is most consistent with the murmur heard in this patient?

A. Aortic regurgitation

B. Aortic stenosis

C. Mitral regurgitation

D. Mitral stenosis

E. Tricuspid regurgitation

F. Tricuspid stenosis

• 
  

Important clues in Step 1 questions about heart murmurs include when the murmur is heard, if it changes with inspiration of air, and where it is best heard.

Urine Concentration and Dilution

Urine Concentration and Dilution

Potassium Homeostasis

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Objectives

1. Describe the signaling mechanisms used in the nervous system.
2. Describe the necessary elements to create an electrochemical gradient.
3. Describe how the membrane and channels work to create the environment necessary for signaling.

Definitions

• ELECTROCHEMICAL GRADIENT: The gradient across a cell membrane created by the differential concentrations of charged ions on either side of the membrane (for example, the difference in concentrations of potassium and sodium ions inside and outside a neuron that when regulated by their respective ion channels allow for signaling down an axon to occur).
• ION CHANNELS: Transmembrane proteins in the cell membrane which open and close to allow for the passage of ions.
• GATING: The process by which channels undergo conformational changes to allow for the passage of ions.
• RESTING MEMBRANE POTENTIAL: The potential created in a neuron at rest by resting channels and sodium-potassium pumps.

Discussion

The nervous system depends on two types of signaling mechanisms, electrical and chemical, to propagate information throughout the nervous system. Rapid changes in the electrical potential across the neuronal cell membrane generate electrical signals that are transmitted down the length of the neuron. This system requires (1) an intact membrane to separate ions and maintain an electrochemical gradient and (2) ion channels to allow for the selective passage of ions of specific charges to generate the electrical signal.

The cell membrane of the neuron is formed by a lipid bilayer and is generally impermeable to charged particles. The double layer of phospholipids is hydrophobic. Charged ions are hydrophilic and as a result attract water molecules. This allows the neuronal cell membrane to separate charges across its surface to maintain the electrochemical gradient. However, to create and use the energy stored in the electrochemical gradient, structures must exist to allow for the passage of ions across this membrane. Ion channels, formed by transmembrane spanning proteins, serve that specific function within the neuron. The basic structure consists of transmembrane proteins with carbohydrate groups attached to their surface and a central pore-forming region to allow for the passage of ions. This pore-forming region spans the entirety of the membrane and is generally made up of two or more subunits.

Ion channels must also be selective for specific charged particles. One method by which channels select for specific ions is by size. Although the diameter of a potassium ion (K+) is larger than the diameter of a sodium ion (Na+), the Na+ ions demonstrate a stronger electrostatic attraction for water molecules. Thus, in a solution the Na+ ion has a larger shell of water than K+ ions. Channels can therefore select for K+ ions based upon the size differential in a solution. Other types of channels are selective for specific ions based upon the ion’s electrical affinity to charged portions of the channel. The attraction between an ion and the channel must be sufficiently strong enough to overcome the hydrostatic attraction of the ion. Once the shell of water surrounding the ion is shed, the ion can diffuse through the channel.

The flow of ions through a channel is passive and governed by the electrochemical gradient. Some ion channels are highly selective for a specific anion or cation, while others are more indiscriminate. Ion channels also open and close based upon the needs of the neuron. This change in state requires a conformational change of the proteins that form the channel, a process called gating.

To understand the electrical properties of the neuron, we must have an understanding of the electrochemical gradient. Particular ions are distributed unequally across the cell membrane. Concentrations of  Na+ and Cl− are greater on the outside of the cell, while concentrations of K+ and organic anions, such as charged amino acids and proteins, are greater on the inside of the cell.

The figure below shows the mechanisms involved in the resting membrane potential across a cell membrane.  There are 2 forces involved -

1) diffusion down concentration gradients

2) diffusion down electrical gradients

At equilibrium, these two forces are equal and opposite.  The example given is for potassium,  K+

At equilibrium, the chemical work = the electrical work.  This equality allows you to rearrange the two equations to solve for membrane potential (Vm).  At 37 C, RT/F = -60 mv.

using normal values from table above, for K+ 
Vm = -60 x log 140/4 = -60 x log35 = -60 x 1.55 =  -93 mv

with hyperkalemia; e.g., Vm = -60 x log 140/6 = -60 x 1.36 = -81.6 mv

with hypokalemia; e.g., Vm = -60 x log 140/2 
= -60 x 1.84 = -110 mv





Goldman Hodgkin Katz Equation



Example with numbers 

Physiology behind EKG effects of hypokalemia and hyperkalemia

In terms of myocardium cell potential:
hyperkalemia = depolarized resting potential, but Decreased excitability.
hypokalemia = hyperpolarized resting potential, but Increased excitability

In terms of EKG surface potential:
hyperkalemia = shortened QT, peaked T wave, wide QRS, ST depression
hypokalemia = prolonged QT, flat Twaves, U waves

Potassium Homeostasis

• Alkalosis leads to shift of K+ into cells = more negative Em (-80 to -90 mV) countered by shift of H+ out of cells. By itself this might make the cell less excitable but the threshold for action potentials also become more negative.

Low serum potassium not only hyperpolarizes most cells, leading to an increase in the resting potential, but also has effects on certain potassium channels required for repolarization. Thus, hypokalemia decreases or slows potassium conductance, the prolonged repolarization phase accounting for the characteristic electrocardiographic findings of broad, flattened T waves. U waves are also indicative of this delay in repolarization . The patient is prone to tachyarrhythmias, including ventricular tachycardia.

• Shift of H+ out of cells leads to increased protein negatively charged binding (Pr-) sites inside cells and in plasma = increased Ca++ binding to these negative sites = decreased contractility

• Net effect = cardiac arrhythmias; muscle weakness

• Acidosis leads to less negative Em (-80 to -70 mV) and shift of K+ out of cells=hyperkalemia

• Partial depolarization produces weaker action potentials and slower spread across myocardium
• Inc. K+ = decreased size of Na+ channels, closure of inactivation gate, slow flux, slower conduction in myocardium; increased permeability to potassium. This decreases heart rate by the same mechanism as acetylcholine, reducing the slope of phase 4 of the sinoartrial node action potential.

• Depolarization decreases excitability because the rate of rise of phase 0 of the action potential (Vmax) is directly proportional to the value of the resting membrane potential at the onset of phase 0. This is because the membrane potential at the onset of depolarization determines the number of sodium channels activated during depolarization, which in turn determines the magnitude of the inward sodium current and the Vmax of the action potential.

As illustrated in Figure 4, Vmax is greatest when the resting membrane potential at the onset of the action potential is approximately −75 mV, and does not increase as the membrane potential becomes more negative. Conversely, as the resting membrane potential becomes less negative (that is, −70 mV), as in the setting of hyperkalemia (Fig. 3), the percentage of available sodium channels decreases. This decrease leads to a decrement in the inward sodium current and a concurrent decrease in the Vmax; therefore, as the resting membrane potential becomes less negative in hyperkalemia, Vmax decreases. This decrease in Vmax causes a slow-ing of impulse conduction through the myocardium and a prolongation of membrane depolarization; as a result, the QRS duration is prolonged.


Hydrogen enters cells in exchange for potassium


This does not occur in respiratory acidosis since CO2 is very lipid soluble and enters cell to produce H+ inside cell. No exchange for K+

• Excess H+ ions interfere with slow Ca++ channels (phase 2) and with binding to troponin C = decreased cardiac contractility
• Net effect = muscle weakness, paralysis, cardiac arrhythmias

Hypokalemia

Potassium is the most abundant monovalent cation in body.  concentration in intracellular space is about the same as that of Na in extracellular space (140 mEq/L).  but the ICF volume is 2x ECF volume so there is twice as much K.

Em sensitive to extracellular K due to relatively small concentrations of K.  Em not sensitive to same magnitude of change in intracellular fluid.

ECF has a total of 70 mEq of K.  A meal may contain 70 mEq K.  Portal vein receives K load, insulin is released, and insulin moves K into cells where the total K is 3500 mEq K.  Then K slowly leaches out into blood to be excreted in urine.

“Ins and Outs” of K

• NaK ATPase constantly bailing Na to keep K inside
• K "bath" used to stop hearts for surgery
• diarrhea loss can be much higher than nl (up to 100 mEq/day)
• creates metabolic acidosis with hypokalemia  (in most cases acidosis comes with hyperkalemia)

• rhabdomyolysis may cause dangerous hyperkalemia

Muscle Weakness from hypokalemia

Hypokalemia will decrease potassium channel conductance, which will lengthen repolarization time of a nerve cell. If this gets to be severe enough, transmission of action potentials will be disrupted, and the result can be generalized weakness or paralysis because signaling to the muscles are disrupted. However, another possibility is cramping, the opposite effect, because of the same reason (being stuck in a depolarized state would also prevent the muscle from relaxing after a contraction was initiated).

In addition, the reduced extracellular potassium (paradoxically) inhibits the activity of the IKr potassium current[11] and delays ventricular repolarization. This delayed repolarization may promote reentrant arrythmias.

K Homeostasis

Kidneys reabsorb all filtered load of K (720 mEq/day) - most in collecting duct (principal cells)

Bartter's Syndrome  - thick ascending limb  = same effect as loop diuretics

Gittleman Syndrome - DCT - resembles thiazide diuretic

Potassium sparing diuretics

• amiloride - Na channel blocker
• reduced aldosterone (ACE inhibitors) or aldosterone receptor blockers (spinolactone)

Physiology in the News - Epi Pens

http://www.wgrz.com/news/local/first-responders-find-alternative-for-costly-epipens/305259463

The results shown in the figure are what happens at a low dose of epi (0.001 mg/min).  At lower circulating concentrations of epi, the major effect on vessels is dilation of arterioles (mainly in skeletal muscle) mediated by activation of beta 2 receptors.  This is also the major response of circulating epi in the fight or flight response.

An epi pen produces higher circulating concentrations of epi (dose is 0.3 mg) which are sufficient to activate alpha-1 receptors, and increase TPR.  If norepi were injected, alpha-1 activation would occur but norepi would not activate beta-2 receptors in the lungs to dilate the airways as an epi pen will do.

Photographic Memory

"You won't find it in the casebook Mr. Brooks, it's just a hypothetical... I am waiting Mr. Brooks."

"Mr. Brooks, did you read this martial?"


"Yes I did read the martial, I memorized the facts, I have a photographic memory-"


"A What?"


"A photographic memory."


"... Would you repeat that?"


"A photographic memory."


"A photographic memory is of absolutely no use to you Mr. Brooks, without the ability to analyze that vast mass of facts between your ears! Did you hear me Brooks?"


"Yes sir."

Case Study - 25 y/o female with cholera

Case Based Learning

You will work on this case in 8 groups of 7 students per group.  The group should discuss all the questions (10 min) and then each member of the group should pick one of the 7 questions to research during the during the next 30 minutes of the first session and submit their answer using this form.  During the last 10 minutes of the first session, the 7 students who researched each question will form a new group (e.g., 7 students who worked on question 1) and take 10 minutes to discuss their individual answers and make plans for coming up with a group consensus answer to be presented during the second session for the case.   During the second session, one or more students from each group will present the answer to their group’s question for 5 minutes followed by 2 minutes for questions from the class.

Pre-study

Video

PowerPoint

Article

Textbook (Costanzo)

Learning Objectives

1. Describe the process and rate-determining factors of passive transport of nonpolar substances; e.g., O2 and CO2, across cell membranes (Fick’s Law of Passive Diffusion).
2. Contrast the features of primary versus secondary active transport across cell membranes and give examples of these transporters in the intestine.
3. Describe the mechanism of water reabsorption in the intestine.
4. Explain the importance of the intestinal sodium glucose co-transporter in the treatment of cholera.
5. Explain how cholera toxin causes loss of body fluids and dehydration.

6. Describe the specific transport processes affected by cholera toxin in the small intestine.

7. Explain the arterial blood gases and acid-base status of this patient.

25 y/o female with diarrhea - case study

A 25 year old female was transported from her rural village to the emergency room at Bujumbura Hospital in Burundi after she developed severe diarrhea, vomiting, and lethargy for 2 days.  

A physician from Medicine Sans Frontiers found her to be afebrile and tachycardic with blood pressure of 85/45 mm Hg.  Tissue turgor was markedly reduced and she had dry mucous membranes and sunken eyes.  Respiratory rate was 20/min. An ECG revealed sinus tachycardia with prolonged QT interval.  Arterial blood gas analysis showed a pH of 7.15; PO2 of 100 mm Hg; and PCO2 of 30 mm Hg.  Blood chemistry showed hematocrit of 45%, Na+ of 140 mEq/L, K+ of 2.5 mEq/L (3.5 – 5.0), Cl- of 100 mEq/L, creatinine of 0.32 mmol/L (0.04 – 0.12), bicarbonate of 10 mEq/L (22-26).   End tidal PCO2 was 30 mm Hg (38-42).  Gram negative bacilli (Vibrio cholerae) were isolated from a stool sample.

She was initially treated with tetracycline and oral administration of a solution with 3.5 g NaCl, 2.5g NaHCO3, 1.5g KCl per L which was not effective in rehydrating the patient.  She was later switched to oral rehydration with World Health Organization (WHO) solution (3.5 g NaCl, 2.5g NaHCO3, 1.5g KCl and 20g glucose per L). Her end-tidal PCO2 was 40 mm Hg and plasma bicarbonate was 24 mEq/L.  Tissue turgor was normal and biochemistry showed K+ of 4 mEq/L, Na+ of 135 mEq/L, Cl- of 104 mEq/L, and creatinine of 0.1 mmol/L.  

She was treated with high dose aspirin (300 mg/kg) to relieve a headache.  This dose proved to be toxic and she developed rapid and deep breathing.  

Please submit your answers to the following using this form.

1. Describe the process and rate-determining factors of passive transport of nonpolar substances; e.g., O2 and CO2, across cell membranes (Fick’s Law of Passive Diffusion).

2. Contrast the features of primary versus secondary active transport across cell membranes and give examples of these transporters in the intestine.

Cholera toxin inhibits all the Na transporters except the Na-glucose cotransporter. Apical = lumen; basolateral = blood side

Big Picture - Glucose transport in enterocytes (line intestine)

3. Describe the mechanism of water reabsorption in the intestine.

4. Explain why the initial rehydration treatment did not work but the second WHO rehydration solution did work.

This picture is of Dr Robert K. Crane and his sketch on a piece of napkin for coupled cotransport that he proposed at the international meetings in Prague in 1960. The sketch shows brush-border membrane supposedly of the intestinal epithelium showing the digestive surface and the diffusion barrier. During digestion the dietary glucose liberated from sucrose at the digestive surface is transported across the plasma membrane by a sodium-glucose carrier complex. Glucose transport is driven by the inward Na+ gradient maintained by the Na+ pump. Strophanthidin inhibits the Na+ pump causing the Na+ gradient to dissipate and remove the driving force for uphill glucose transport. Phlorizin inhibits cotransport. The model remains valid to this day, apart from some minor details such as the site of phlorizin inhibition (extracellular) and the location of the Na+/K+ pump.

5. Describe the rationale for the composition of the World Health Organization oral rehydration fluid.

5. Explain how cholera toxin causes loss of body fluids and dehydration.

Cholera toxin has binding and enzymatically active subunits that activate the adenylate cyclase system of cells in the intestinal mucosa leading to increased levels of intracellular cAMP (11). The effect is dependent on a specific receptor, a monosialoganglioside (GM1), present on the luminal surface of epithelial cells. The A1 subunit of the toxin, once it enters the cell, enzymatically transfers ADP-ribose from NAD to the αS-subunit of a stimulatory G protein (GS). When ADP-ribose is bound, the intrinsic GTPase activity of the αS-subunit is inhibited and the GTP-coupled form is permanently activated. Once activated, the αS-subunit of the GS attaches to the catalytic subunit of adenylate cyclase and leads to its continuous activation producing abnormally high levels of cAMP.

6. Describe the specific transport processes affected by cholera toxin in the small intestine.

Intestinal crypt cells, the primary secretory cells found in the small intestinal mucosa, respond to numerous secretagogues including acetylcholine, prostaglandins, and vasoactive intestinal peptide and the second messengers Ca2+ and cAMP to lead to chloride secretion through CFTRs located on the apical (luminal) side of the cells (see Fig. 1). In the presence of cholera toxin, chloride transport into the intestinal lumen through CFTRs located on the luminal surface of intestinal crypt cells is continuously activated by intracellular cAMP causing osmotic diarrhea drawing water into the lumen and leading to the characteristic large volumes of watery diarrhea

   

This model of NaCl transport across ductal cells in sweat glands of normal and CF individuals demonstrates the differences in salt reabsorption there that leads to the elevated sweat NaCl in CF patients. Na+ ions utilize ENaCs to enter the cells from the luminal side and Na+-K+-ATPases to leave the cells on the blood side. Cl− ions predominantly utilize CFTRs to enter the cells from the luminal side and other Cl− transporters to leave the cells on the blood side. In CF, the lack of functional CFTRs on the luminal side of the cell compromises the movement of cationic Na+ ions and its accompanying anionic Cl− ions leading to less reabsorption of salt out of the lumen. Salt concentrations in CF sweat can be up to 3–5 times normal. (Modeled after Figure 1 in Ref. 27.)

7. Explain the arterial blood gases and acid-base status of this patient.

http://advan.physiology.org/content/29/2/75