Merry Christmas

Merry Christmas

&

Happy New Year

from Steve & Linda Wood

Cardiac Cycle Tutorial

click on:

Cardiac Cycle Tutorial

Evidence Based Medicine

Evidence Based Medicine

How to Write Learning Objectives, USMLE Step 1 MCQs, and Confidence Based Practice Questions

click below for slides

How to Write Learning Objectives, USMLE Step 1 MCQs, and Confidence Based Practice Questions

2016/17

Steve Wood, PhD

How to Study in Medical School

How to Study in Medical School

What worked in undergraduate school (did well on the exam but forgot the material quickly) which was OK because you didn't need to use it again: Cram

What you need to do in medical school (do well on the exam AND remember the material for other modules and for Step1): study and re-study!


No pain, No gain (applies to learning too)

Use all the learning styles (even if they are not your preferred style)

Respiratory Failure

Respiratory Failure

Memory Tool:  Type 2 = CO2

Excerpts from the novel "Oxygen"

The entire complex human machine pivots on the pinnacle of oxygen. The bucket brigade of energy metabolism that keeps us all alive ends with oxygen as the final electron acceptor. Take it away, and the cascade clogs up in minutes, backing up the whole precisely tuned engine until it collapses, choked, cold and blue. 

Two portals connect us to oxygen—the mouth and the nose—appreciated more for all their other uses: tasting, smelling, smiling, whistling, blowing smoke and blowing kisses, supporting sunglasses and lipstick designers, perfumeries and plastic surgeons. Seal them for the duration of the morning weather report and everything you had planned for the rest of your life evaporates in a puff of imagination.



From the novel, Oxygen
By Carol Wiley Cassella, MD

Venn Diagrams for Medical Students

Step 1 Practice Questions

1. A 12-year-old male refugee from Haiti is being examined by a physician working for Médecins sans frontières.  Auscultation of the heart reveals no audible sounds but pulse exam in normal.  Electrocardiogram is normal except for an extreme axis deviation. Chest X-ray was obtained (see figure). Which of the following is a complication of this condition that the patient is most likely to develop?



A. Bronchiectasis
B. Heart failure
C. Mitral valve prolapse
D. Pneumothorax
E. Small bowel obstruction

History of Blood Pressure Measurement

Hall, W. D. (1987). "Stephen Hales: theologian, botanist, physiologist, discoverer of hemodynamics". Clinical Cardiology. 10 (8): 487–9.

Reverend Stephen Hales was the first person to measure blood pressure.  He did this in 1733 using a glass tube inserted in the carotid artery of a sedated horse.  The artist chose to depict the tube coming out of the horse's neck but it was actually in the groin:  “In December I caused a mare to be tied down alive on her back … having laid open the left crural artery about three inches from her belly, I inserted into a brass pipe whose bore was one-sixth of an inch in diameter and to that by means of another brass pipe which was fitly adapted to it, I fixed a glass tube of nearly the same diameter which was nine feet in length. Then , untying the ligature on the artery, the blood rose in the tube to eight feet in length, three inches perpendicular above the level of the left ventricle of the heart”.

8 feet 3 inches = 99 inches of blood = 185 mmHg blood pressure

Water Movement across Membranes

'Fluid Physiology' by Kerry Brandis -from http://www.anaesthesiaMCQ.com

Fluid Physiology

1.2 Water Movement across Membranes

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1.2.1 Pathways for Water Movement

Oil & water don't mix

Water and lipids are the two major types of solvent in the body. The lipid cell membrane separates the intracellular fluid from the extracellular fluid (as discussed in Section 2.1). Substances which are water soluble typically do not cross lipid membranes easily unless specific transport mechanisms are present. It might be expected that water would likewise not cross cell membranes easily. Indeed, in artificial lipid bilayers, water does not cross easily and this is consistent with our expectation.

. . . but paradoxically, water crosses nearly all the membranes in the body with ease!

Two questions spring immediately to mind:

• How can this be so?
• How does it happen? (ie. What is the route & mechanism by which water crosses membranes?)

The answer to this problem:

Water molecules cross cell membranes by 2 pathways which we can call the lipid pathway & the water channel pathway.

What is the 'lipid pathway'?

This refers to water crossing the lipid bilayer of the cell membrane by diffusion. This initially does not seem to be very credible based on the 'oil & water don't mix' idea BUT it is nonetheless extremely important because this pathway is available in ALL cells in the body.

To express this slightly differently: The 'oil & water don't mix' idea can be quantified as the partition coefficient (i.e., concentration of water in the lipid phase to the concentration in the aqueous phase). This partition coefficient is as expected, extremely low: about 10-6 which is 1 to a million.

Now there are a couple of other equally important facts to consider:

• the concentration of water in water is extremely high
• the surface area of the cell membrane is very large (relative to the contained volume)

These factors must be included when considering diffusion across the membrane (as quantified by Fick's law of Diffusion) and they significantly counteract the the very low permeability.

The lipid composition of different cell membranes varies so the rate of fluid flow across cell membranes does vary.

What is the 'water channel' pathway?

In some membranes the water flux is very high and cannot be accounted for by water diffusion across lipid barriers. A consideration of this fact lead to the hypothesis that membranes must contain protein which provide an aqueous channel through which water can pass. The water channels have now been found and are discussed below. Flow of water through these channels can occur as a result of diffusion or by filtration.

What other factors are important for the passage of water across membranes?

The above discussion refers to water moving from one side of a lipid barrier to the other and this is relevant to the cell membrane. Other 'membranes' need to be considered; in particular the capillary membrane & the lymphatic endothelial membrane. These are tubular sheets of very many endothelial cells, each with their own cell membrane, but also with a potential pathway for water & solutes existing at the junction of adjacent cells. Similarly all epithelial cell layers can be considered as 'membranes' through which water passes and these also have intercellular pathways.

1.2.2 Capillary Membranes

Water can cross capillary membranes via:

• the intercellular gaps between the endothelial cells
• pores in the endothelial cells special areas where the cytoplasm is so thinned out that it produces deficiencies known as fenestrations.
• diffusion across the lipid cell membranes of the endothelial cells

Intercellular slits in the capillary membrane have a diameter of about 7 nm which is much larger than the 0.12 nm radius of a water molecule. Because the total surface area of the body’s capillaries is huge (6,300 m2) and their walls are thin (1 mm), the total diffusional water flux across the capillaries in the body is very large indeed. (See Section 4.1). Normally this diffusional exchange does not represent any net flow in either direction because the water concentration on both sides of the capillary membrane is the same.

Fenestrations are found only in capillaries in special areas where a very high water permeability is necessary for the function of these areas. A high water permeability is clearly necessary in the glomerular capillaries and water permeability here is very much higher than in muscle capillaries. Other areas with fenestrations are the capillaries in the intestinal villi and in ductless glands.

Water also easily enters the lymphatic capillaries via gaps between the lymphatic endothelial cells. These gaps function also as flap valves and this also promotes forward lymph flow when the capillaries are compressed.

In other areas of the body the water permeability of capillary membranes is quite low. An example is the blood-brain barrier. The capillary endothelial cells here are joined by tight junctions which greatly limit water movement by the intercellular pathway.

1.2.3 Aquaporins: Cell Membrane Water Pores

The presence of specific pores (channels) in the cell membrane has long been predicted but the proteins involved in these water channels have only recently been characterised. At present at least 6 different water channel proteins (named aquaporins) have been found in various cell membranes in humans. These aquaporin proteins form complexes that span the membrane and water moves through these channels passively in response to osmotic gradients. These channel proteins are present in highest concentrations in tissues where rapid transmembrane water movement is important (eg in renal tubules).

Aquaporin 0 is found in the lens in the eye. It has a role in maintaining lens clarity. The gene for this protein is located on chromosome 12.

Aquaporin 1 (previously known as CHIP28) is present in the red cell membrane, the proximal convoluted tubule and the thin descending limb of the Loop of Henle in the kidney, secretory and absorptive tissues in the eye, choroid plexus, smooth muscle, unfenestrated capillary endothelium, eccrine sweat glands, hepatic bile ducts and gallbladder epithelium. The Colton blood group antigen is located on extracellular loop A of aquaporin 1 in red cells. The gene is located on chromosome 7.

Aquaporin 2 is the ADH-responsive water channel in the collecting duct in the inner medulla. Insertion of the channel into the apical membrane occurs following ADH stimulation. The gene is located on chromosome 12.

Aquaporins 3 and 4 are present in the basolateral membrane in the collecting duct. They are not altered by ADH levels. Recently, aquaporin 4 has been found in the ADH-secreting neurones of the supraoptic and paraventricular nuclei in the hypothalamus and it has been suggested that it may be involved in the hypothalamic osmoreceptor which regulates body water balance. (See Section 5.3). The gene for aquaporin 3 is located on chromosome 7.

Aquaporin 5 is found in lacrimal and salivary glands and in the lung. It may be the target antigen in Sjogren’s syndrome.

The aquaporins all have a similar topology consisting of 6 transmembrane domains

Aquaporin research is currently an active field. These proteins have been identified in all living organisms. New aquaporin inhibitors may prove to be useful diuretic agents. Mercurial compounds used to treat syphilis were noted in 1919 to have a diuretic action. More potent mercurial diuretics were subsequently developed and were once used widely until replaced by less toxic diuretics. These mercurial diuretics act by binding to a specific site on aquaporin 2 with blocking of renal water reabsorption. (See Section 5.6)

1.2.4 Effect on Cell Volume

The movement of water across cell membranes is essential for cellular integrity but can cause problems. A small difference in solute concentration results in a very large osmotic pressure gradient across the cell membrane and the cell membranes of animal cells cannot withstand any appreciable pressure gradient. Water movement can eliminate differences in osmolality across the cell membrane but this alone is itself a problem as it leads to alteration in cell volume. Consequently regulation of intracellular solute concentration is essential for control of cell volume.

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'Fluid Physiology' by Kerry Brandis -from http://www.anaesthesiaMCQ.com

Cardiovascular Study Questions

Cardiovascular Study Questions

This Qbank is under construction - more questions will be coming

Righty Tighty - Lefty Loosey

Share your favorite memory tools here

Practice Questions: Cell Electrophysiology

Practice Questions: Cell Electrophysiology

Treatment of Iron Deficiency - Risks

Iron overdose as a cause of a high anion gap metabolic acidosis

Now, iron is usually mentioned as an important cause of metabolic acidosis, and there is a warm spot reserved for it in the “MUDPILES” mnemonic. An impressionable person might be inclined to believe that iron contributes to the high anion gap metabolic acidosis by dissociating into unmeasured anions, much like the toxic alcohols. However, that would be wildly inaccurate, because iron is a cation.

The acidosis here is multifactorial. Some textbooks (Fowler’s Handbook on the Toxicology of Metals) suggest that the acidosis is mainly due to the physicochemical effects of the iron ion itself. Other sources (Goldfranks Manual of Toxicologic Emergencies) attribute the acidosis to a raised lactate, of which not all is generated by direct effects of the iron, but rather due to the fluid loss (from an ulcerated gut), cardiogenic shock (due to the myocardial mitochondrial toxicity) and fulminant hepatic failure. On top of that, a fair portion of  the lactic acidosis is due to the direct mitochondrial toxicity of iron in all tissues.

 

http://www.derangedphysiology.com/main/core-topics-intensive-care/acid-base-disturbances/Chapter%206.2.0/iron-overdose

Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value

source: https://onlinecourses.science.psu.edu/stat507/node/71

In this example, two columns indicate the actual condition of the subjects, diseased or non-diseased. The rows indicate the results of the test, positive or negative.

Cell A contains true positives, subjects with the disease and positive test results. Cell D subjects do not have the disease and the test agrees.

A good test will have minimal numbers in cells B and C.  Cell B identifies individuals without disease but for whom the test indicates 'disease'. These are false positives. Cell C  has the false negatives.

If these results are from a population-based study, prevalence can be calculated as follows:

• Prevalence of Disease=  T_disease/ Total × 100

The population used for the study influences the prevalence calculation.

Sensitivity is the probability that a test will indicate 'disease' among those with the disease:

• Sensitivity: A/(A+C) × 100

Specificity is the fraction of those without disease who will have a negative test result:

• Specificity: D/(D+B) × 100

Sensitivity and specificity are characteristics of the test. The population does not affect the results.

A clinician and a patient have a different question: what is the chance that a person with a positive test truly has the disease? If the subject is in the first row in the table above, what is the probability of being in cell A as compared to cell B? A clinician calculates across the row as follows:

• Positive Predictive Value: A/(A+B) × 100
• Negative Predictive Value: D/(D+C) × 100

Positive and negative predictive values are influenced by the prevalence of disease in the population that is being tested. If we  test in a high prevalence setting, it is more likely that persons who test positive truly have disease than if the test is performed in a population with low prevalence..

Let's see how this works out with some numbers...

Hypothetical Example 1 - Screening Test A

100 people are tested for disease. 15 people have the disease;  85 people are not diseased.  So,  prevalence is 15%:

• Prevalence of Disease:
  T_disease/ Total × 100,
  15/100 × 100 = 15%

Sensitivity is two-thirds, so the test is able to detect two-thirds of the people with disease. The test misses one-third of the people who have disease.

• Sensitivity:
  A/(A + C) × 100
  10/15 × 100 = 67%

The test has 53% specificity. In other words, 45 persons out of 85 persons with negative results are truly negative and 40 individuals test positive for a disease which they do not have.

• Specificity:
  D/(D + B) × 100
  45/85 × 100 = 53%

The sensivity and specificity are characteristics of this test. For a clinician, however, the important fact is among the people who test positive, only 20% actually have the disease.

• Positive Predictive Value:
  A/(A + B) × 100
  10/50 × 100 = 20%

For those that test negative, 90% do not have the disease.

• Negative Predictive Value:
  D/(D + C) × 100
  45/50 × 100 = 90%

Now, let's change the prevalence..

Hypothetical Example 2 - Increased Prevalence, Same Test

This time we  use the same test, but in a different population, a disease prevalence of 30%.

• Prevalence of Disease:
  T_disease/ Total × 10
  30/100 × 100 = 30%

We maintain the same sensitivity and specificity because these are characteristic of this test.

• Sensitivity:
  A/(A + C) × 100
  20/30 × 100 = 67%

• Specificity:
  D/(D + B) × 100
  37/70 × 100 = 53%

Now let's calculate the predictive values:

• Positive Predictive Value:
  A/(A + B) × 100
  20/53 × 100 = 38%

• Negative Predictive Value:
  D/(D + C) × 100
  37/47 × 100 = 79%

Using the same test in a population with higher prevalence increases  positive predictive value. Conversely, increased prevalence results in decreased negative predictive value. When considering predictive values of diagnostic or screening tests, recognize the influence of the prevalence of disease. The figure below depicts the relationship between disease prevalence and predictive value in a test with 95% sensitivity and 95% specificity:

Relationship between disease prevalence and predictive value in a test with 95% sensitivity and 85% specificity.
(From Mausner JS, Kramer S: Mausner and Bahn Epidemiology: An Introductory Text. Philadelphia, WB Saunders, 1985, p. 221.)

Think About It!

Come up with an answer to this question and then click on the icon to the left to reveal the answer.

Under what circumstance would you really want to minimize the false positives?

 answer: Minimizing false positives is important when the costs or risks of followup therapy are high and the disease itself is not life-threatening...prostate cancer in elderly men is one example; as another, obstetricians must consider the potential harm from a false positive maternal serum AFP test (which may be followed up with amniocentesis, ultrasonography and increased fetal surveillance as well as producing anxiety for the parents and labeling of the unborn child), against potential benefit.

Think About It!

Come up with an answer to this question and then click on the icon to the left to reveal the answer.

When would you want to minimize the false negatives?

answer: We don’t want many false negative if the disease is often asymptomatic and

1. is serious, progresses quickly and can be treated more effectively at early stages OR
2. easily spreads from one person to another

What is a good test in a population?  Actually, all tests have advantages and disadvantages, such that no test is perfect.  There is no free lunch in disease screening and early detection.

Cramps

Cramps

Causes

Overuse of a muscle, dehydration, muscle strain or simply holding a position for a prolonged period can cause a muscle cramp. In many cases, however, the cause isn't known - idiopathic.

Although most muscle cramps are harmless, some may be related to an underlying medical condition, such as:

• Inadequate blood supply. Narrowing of the arteries that deliver blood to your legs (arteriosclerosis of the extremities) can produce cramp-like pain in your legs and feet while you're exercising. These cramps usually go away soon after you stop exercising.
• Nerve compression. Compression of nerves in your spine (lumbar stenosis) also can produce cramp-like pain in your legs. The pain usually worsens the longer you walk. Walking in a slightly flexed position — such as you would use when pushing a shopping cart ahead of you — may improve or delay the onset of your symptoms.
• Mineral depletion. Too little potassium, calcium or magnesium in your diet can contribute to leg cramps. Diuretics — medications often prescribed for high blood pressure — also can deplete these minerals.

Neuromuscular Cramps 

Possible roles of calcium and ATP in muscle cramps.  Too little ATP means calcium stays in the sarcoplasma and muscles stay contracted.  ischemia = low oxygen = low ATP

Practice Questions - Cell Electrophysiology

the link below is to a set of practice questions on 
cell electrophysiology - this is updated with more questions and scoring (9/25/16)



Cell Physiology Practice Questions


after you do the practice questions you submit your answers and you will see your results as well as a summary of the responses of students who have taken the quiz.  

There is also a link to an explanation of the answers

Case study; 17 y/o male with muscle weakness - Case and answers

17 y/o male with muscle weakness   

Case Authors:  Steve Wood, PhD

Tracey Milligan, MD

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.

Learning Objectives

1. Draw a concept map and explain the mechanisms (hormonal, renal, cellular) involved in potassium homeostasis.
2. Draw and label the phases of an action potential for a skeletal muscle cell, cardiac muscle cell, and sinoatrial node.  
3. Describe the effects of hypokalemia and hyperkalemia on the resting membrane potential and potassium conductance of cells including nerve and muscle.
4. Describe how surreptitious use of diuretics can cause hypokalemia and explain how one diuretic (acetazolamine) can be used to treat hypokalemia.
5. Explain the mechanisms of muscle weakness in hypokalemia.
6. Describe the genetics and molecular mechanisms of hypokalemic periodic paralysis.
7. Explain the mechanisms that lead to transcellular shifts of potassium. Describe how marijuana intoxication may lead to hypokalemia.
8. Bonus question (anybody can do this one):  Explain the abnormal findings on the EKG.

Pre-study

Strong Medicine - video

Potassium Homeostasis (blog)

Costanzo - sections on membrane potential, Nernst equation, etc.

Hypokalemic periodic paralysis attack - video

Gordon Hu is a 17-year-old member of his high school wrestling team.  He is 5’ 10” tall and competes in the 145 - 150 lb. division.  He struggles to make this weight for matches as his weight is normally 160 lbs.  He is extremely muscular and exercises frequently outside of practice including cardio and strength training.  He doesn’t drink or smoke cigarettes but does smoke marijuana with his friends.

He knew it was normal to be tired and feel weak after a hard practice or match, but lately he had noticed extreme weakness and his legs felt “like rubber”.  He thought that maybe he had low blood sugar so he made it a point to do some “carb loading” before a match.  Instead of improving his symptoms, this seemed to make them worse.  After his most recent match, he had to carried off the mat after he was pinned, suffering his 3rd straight loss.  After he collapsed, Gordon was terrified when he discovered that although he was conscious, he couldn’t open his eyes or speak for about 30 seconds; then he was o.k. but still had to be helped off the mat.

Gordon’s parents were at the wrestling match and were very alarmed at what had happened.  His father remembered having similar problems when he was a high school athlete.  They told Gordon they were going to make an appointment with the family doctor.  The next morning, they met with Dr. Rhodes, their family physician.  Dr. Rhodes talked to Gordon about his problem and made the following notes on Gordon’s chart:

Gordon’s symptoms were recent onset.  He did not have any problems like this when he was a child.  He started noticing some weakness after he went out for wrestling in 10th grade (2 years ago).  The problem only occurred once in awhile.  Sometimes he would have no problems for 6 months, and then experience weakness several times a month.  Gordon has no siblings.  He reports having several girlfriends and is sexually active.  No recent travel.  Childhood illnesses were chickenpox, mumps, and measles.  Physical exams have been normal.  Denies cigarette and alcohol use.  He smokes marijuana “occasionally”.  Due to physique, inquiry was made re: steroid use.  Pt. denies using any steroids.  Gordon’s father reported similar problems when he was involved in high school athletics.  He remembered that some “supplement” prescribed by the family doctor made it better.

Dr. Rhodes took a blood sample and sent it to the lab next door for a CBC and electrolyte panel.  He also took a muscle biopsy for testing.  While waiting for the results he did a physical exam:

Physical Exam

General  -  healthy young man, alert, oriented.  

Vital signs

Oxygen saturation  98%

Blood pressure  120/80 mm Hg

Pulse 66 beats per minute

Respiration  12 bpm

Weight  160 lbs

Height  5 ft. 10 in

Body mass index 28.4  (click on link to go to calculator)

Temperature  98.6 F

Laboratory Tests/Investigations

CBC  

Hb 15 g/dL (normal 14-18 g/dL)

Hct 45 % (normal 42-52%)

White blood count (WBC) 12 x 103   (normal 5-10 x 103/mm3)

Neutrophils – elevated

Lymphocytes – nl

Monocytes - nl

Eosinophils – nl

Basophils - nl

Platelets  450,000 (normal 150,000 – 400,000/mm3)

Electrolytes

Na+ - 135 (normal 135 – 145 mEq/L)

K+  -   4.4 (normal 3.5 – 5 mEq/L)

Cl- -   110 (normal 100 – 110 mEq/L)

Because the test results were mostly normal, Dr. Rhodes decided to repeat the blood test after Gordon had done 40 pushups in the office.  The electrolyte results were:

Electrolytes

Na+ 135 (normal 135 – 145 mEq/L)

K+ 2.2 (normal 3.5 – 5 mEq/L)

Cl-  110 (normal 100 – 110 mEq/L)

A 12 lead EKG was obtained because of the low K+

Normal EKG

Dr. Rhodes told Gordon that he has a condition called hypokalemic periodic paralysis.  He explained that there is no cure but it can be treated.  He explained that it is an inherited trait due to a gene mutation.  

Discuss the following questions/learning issues and each member pick 1 of them for presentation during the second session.  Submit your answers using this form.

1. Draw a concept map and explain the mechanisms (hormonal, renal, cellular) involved in potassium homeostasis.

Also, to amplify the renin-angiotensin-aldosterone system:



High potassium is one of the signals that stimulates production of renin which catalyzes the conversion of angiotensinogen to angiotensin I to start the signalling pathway.

2. Draw and label the phases of an action potential for a neuron, skeletal muscle cell, cardiac muscle cell, and sinoatrial node.  

3. Describe the effects of hypokalemia and hyperkalemia on the resting membrane potential and potassium conductance of cells including nerve and muscle.

Hyperkalemia effects on cardiac muscle action potentials are summarized in this figure:  During phase 4, the resting membrane potential is depolarized (less negative) according to the Nernst equation  

Phase 0 of the action potential occurs when voltage gated sodium channels open and sodium enters the myocyte down its electrochemical gradient. 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. 

Hyperkalemia also has profound effects upon phase 2 and phase 3 of the action potential. After the rapid influx of sodium across the cell membrane in phase 0, potassium ions leave the cell along its electrochemical gradient, which is reflected in phase 1 of the action potential. As the membrane potential reaches –40 to –45 mV during phase 0, calcium channels are stimulated, allowing calcium to enter the myocyte. The maximum conductance of these channels occurs approximately 50 msec after the initiation of phase 0 and is reflected in phase 2 of the action potential.
During phase 2, potassium efflux and calcium influx offset one another so that the electrical charge across the cell membrane remains the same, and the so-called plateau phase of the action potential is created (Fig. 3). During phase 3, the calcium channels close, while the potassium channels continue to conduct potassium out of the cell; in this way, the electronegative membrane potential is restored.7 One of the potassium currents (Ikr), located on the myocyte cell membrane, is mostly responsible for the potassium efflux seen during phases 2 and 3 of the cardiac action potential.10 For reasons that are not well understood, these Ikr currents are sensitive to extracellular potassium levels, and as the potassium levels increase in the extracellular space, potassium conductance through these currents is increased so that more potassium leaves the myocyte in any given time period.10 This leads to an increase in the slope of phases 2 and 3 of the action potential in patients with hyperkalemia and therefore, to a shortening of the repolarization time. This is thought to be the mechanism responsible for some of the early electrocardiographic manifestations of hyperkalemia, such as ST-T segment depression, peaked T waves, and Q-T interval shortening.


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 slowing of impulse conduction through the myocardium and a prolongation of membrane depolarization; as a result, the QRS duration is prolonged.

Hypokalemia would hyperpolarize the resting membrane potential but this does not change the slope of phase 0 as the Vmax does not change (Fig. 4).

Causes of Hyperkalemia 
Numerous causes of hyperkalemia are seen in clinical practice. The most common are renal disease and the ingestion of medications that predispose the patient to hyperkalemia.2 Medications known to cause hyperkalemia include angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, penicillin G, trimethoprim, spironolactone, succinylcholine, alternative medicines, and heparin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413606/pdf/20060300s00010p40.pdf

4. Describe how surreptitious use of diuretics can cause hypokalemia and explain how one diuretic (acetazolamine) can be used to treat hypokalemia.

CA inhibitors, like acetylzolamide, are effective in many cases of Hypokalemic periodic paralysis.  This is at first a paradox because CA inhibitors cause potassium loss and hypokalemia.  However, CA inhibitors also impair bicarbonate reabsorption in the renal tubules.  The resulting urinary loss of bicarb causes metabolic acidosis.  The increased hydrogen ion causes a shift of potassium out of cells, alleviating the hypokalemia. Also results in less Ca++ binding to Protein-, increasing contractability.

5. Explain the mechanisms of muscle weakness in hypokalemia.

• Low potassium causes vasoconstriction and reduced muscle blood flow, leading to lactic acid accumulation in muscles.  This causes osmotic entry of water which impairs calcium channels.  Reduced calcium movement impairs contraction.
• 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.

Hyperkalemia also causes muscle weakness:

It might be expected that this depolarization would make it easier to generate action potentials in the muscle because the resting membrane potential would be closer to threshold. A more important effect of depolarization, however, is that it closes the inactivation gates on Na + channels. When these inactivation gates are closed, no action potentials can be generated, even if the activation gates are open. Without action poten­tials in the muscle, there can be no contraction.

6. Describe the genetics and molecular mechanisms of hypokalemic periodic paralysis.

The physiologic basis of flaccid weakness is inexcitability of the muscle membrane (ie, sarcolemma). Alteration of serum potassium level is not the principal defect in primary PP; the altered potassium metabolism is a result of the PP. In primary and thyrotoxic PP, flaccid paralysis occurs with relatively small changes in the serum potassium level, whereas in secondary PP, serum potassium levels are markedly abnormal.

The sodium channel has 2 gates (activation and inactivation) and can exist in 3 states. At rest with the membrane polarized, the activation gate is closed and the inactivation gate is opened. With depolarization, the activation gate opens, allowing sodium ions to pass through the ion channel and also exposing a docking site for the inactivation gate. With continued depolarization, the inactivation gate closes, blocking the entry of sodium into the cell and causing the channel to enter the fast-inactivation state. This inactivation of the channel allows the membrane to become repolarized, resulting in a return to the resting state with the activation gate closed and the inactivation gate opened. Two inactivation processes occur in mammalian skeletal muscle: Fast inactivation involves terminating the action potential and acts on a millisecond time scale. Slow inactivation takes seconds to minutes and can regulate the population of excitable sodium channels.

Sodium channel mutations that disrupt fast and slow inactivation are usually associated with a phenotype of HyperPP and myotonia, where as mutations that enhance slow or fast inactivation producing loss of sodium channel function cause HypoPP.

some forms of HypoPP involve mutations of calcium and/or potassium channels.

7. Explain the mechanisms that lead to transcellular shifts of potassium. Describe how marijuana intoxication may lead to hypokalemia.

Electrolyte abnormalities reported in marijuana users contribute to pathology. Chronic marijuana users have lower serum sodium and potassium than non-users.[17] The heavy consumption of carbohydrates while intoxicated leads to an increase in serum insulin levels, driving potassium into cells and causing serum hypokalemia.[18]

The heavy consumption of carbohydrates while intoxicated leads to an increase in serum insulin levels, driving potassium into cells and causing serum hypokalemia.[18] This hypokalemia can produce reentrant arrhythmias by decreasing conductivity and increasing the resting membrane potential, duration of the action potential, and duration of the refractory period.[19] EKG changes include the decrease in T-wave amplitude, presence of U waves and a prolonged QTc.

Memory tool: Al Klow sis

8. Bonus question (anybody can do this one):  Explain the abnormal findings on the EKG.

This hypokalemia can produce reentrant arrhythmias by decreasing conductivity and increasing the resting membrane potential, duration of the action potential, and duration of the refractory period.[19] EKG changes include the decrease in T-wave amplitude, presence of U waves and a prolonged QTc.

The decrease in Vmax in hyperkalemia causes a slowing of myocardial conduction, manifested by progressive prolongation of the P wave, PR interval, and QRS complex.

The maximum conductance of these channels occurs approximately 50 msec after the initiation of phase 0 and is reflected in phase 2 of the action potential. During phase 2, potassium efflux and calcium influx offset one another so that the electrical charge across the cell membrane remains the same, and the so-called plateau phase of the action potential is created (Fig. 3). During phase 3, the calcium channels close, while the potassium channels continue to conduct potassium out of the cell; in this way, the electronegative membrane potential is restored.7 One of the potassium currents (Ikr), located on the myocyte cell membrane, is mostly responsible for the potassium efflux seen during phases 2 and 3 of the cardiac action potential.10 For reasons that are not well understood, these Ikr currents are sensitive to extracellular potassium levels, and as the potassium levels increase in the extracellular space, potassium conductance through these currents is increased so that more potassium leaves the myocyte in any given time period.10 This leads to an increase in the slope of phases 2 and 3 of the action potential in patients with hyperkalemia and therefore, to a shortening of the repolarization time. This is thought to be the mechanism responsible for some of the early electrocardiographic manifestations of hyperkalemia, such as ST-T segment depression, peaked T waves, and Q-T interval shortening.