t 3 harder

 chloride- bicarb exchange mechanism

Occurs mainly in red blood cells.

Steps

CO₂ enters the red blood cell

↓

Carbonic anhydrase converts CO₂ + H₂O

↓

Carbonic acid

↓

H⁺ + HCO₃⁻

↓

Bicarbonate leaves the red blood cell

↓

Chloride enters

This is called the chloride shift.

In the lungs, the process reverses so CO₂ can be exhaled.

Sodium and chloride transport

Sodium Transport 1. Na⁺/Glucose (or other solute) Cotransport

• Na⁺ enters the enterocyte with glucose, amino acids, or some B vitamins.

• Na⁺/K⁺-ATPase pumps Na⁺ into the blood.

• Glucose leaves by facilitated diffusion.

Remember: Na⁺ + glucose enter together.

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2. Electroneutral Na⁺/Cl⁻ Absorption

• Na⁺/H⁺ exchanger brings Na⁺ into the cell.

• Cl⁻/HCO₃⁻ exchanger brings Cl⁻ into the cell.

• Na⁺ is pumped into the blood by the Na⁺/K⁺-ATPase.

• Cl⁻ diffuses to the blood (mostly paracellular).

Remember: Na⁺ in for H⁺, Cl⁻ in for HCO₃⁻.

---

3. Electrogenic Na⁺ Absorption

• Na⁺ enters through a Na⁺ channel.

• Na⁺/K⁺-ATPase pumps Na⁺ into the blood.

• Water and anions follow Na⁺.

• Most common in the colon.

Remember: Na⁺ channel → Na⁺ pump → water follows.

---

Chloride (Cl⁻) Transport 1. Na⁺/Glucose Cotransport

• Cl⁻ follows Na⁺ to maintain electrical neutrality.

2. Electroneutral Na⁺/Cl⁻ Absorption

• Cl⁻ enters through the Cl⁻/HCO₃⁻ exchanger.

• Cl⁻ then diffuses into the blood.

3. Electrogenic Na⁺ Absorption

• Cl⁻ passively follows Na⁺.

• Water also follows.

---

Chloride Secretion (Know This Too)

Basolateral membrane:

• Na⁺/K⁺-ATPase

• Na⁺/K⁺/Cl⁻ cotransporter (NKCC)

• K⁺ channels

Apical membrane:

• CFTR secretes Cl⁻ into the intestinal lumen.

• Na⁺ and water follow → NaCl and fluid secretion.

• Cholera and E. coli increase cAMP/Ca²⁺ → stimulate CFTR → diarrhea.

Easy way to memorize

Sodium

1. Na⁺ + glucose

2. Na⁺/H⁺ + Cl⁻/HCO₃⁻

3. Na⁺ channel

Chloride

• Follows sodium in all three absorption pathways.

• CFTR secretes chloride into the gut → water follows → diarrhea if overstimulated.

RAAS (Renin-Angiotensin-Aldosterone System)What stimulates RAAS?

• Low blood pressure

• Low blood volume

• Low kidney perfusion

• Increased sympathetic activity (catecholamines)

RAAS (Renin-Angiotensin-Aldosterone System) sequence

• Low blood pressure/volume

• Kidney releases Renin

• Renin converts Angiotensinogen → Angiotensin I

• ACE converts Angiotensin I → Angiotensin II

• Angiotensin II stimulates the release of Aldosterone from the adrenal gland.

Angiotensin II causes these to happen

• Vasoconstriction

• Increased blood pressure

• Increased thirst

• Increased ADH release

• Increased aldosterone release

• Decreased sodium loss

Aldosterone Released from

the adrenal gland

Aldosterone Functions

acts on kidney

• Increases sodium reabsorption

• Increases chloride reabsorption

• Increases potassium excretion

• Water follows sodium

• Increases blood volume

• Increases blood pressure

Low BP or low blood volume → Renin → Angiotensin I → ACE → Angiotensin II → Aldosterone

Angiotensin II

• Vasoconstriction

• ADH ↑

• Thirst ↑

• Aldosterone ↑

Aldosterone

• Na⁺ ↑

• Cl⁻ ↑

• Water ↑

• K⁺ ↓

• Blood pressure ↑

steps to restore osmolarity when water balance changes and what occurs when water balance changes

hypervolemic and hypovolemic

what happens in a hypovolemic state to restore balance?

Hypovolemia (low blood volume)Causes

• Vomiting

• Diarrhea

• Blood loss

• Sweating

• Dehydration

Sequence

Blood volume ↓

↓

ECF osmolarity ↑

↓

Hypothalamic osmoreceptors detect the change

↓

ADH (vasopressin) is released

↓

Kidneys reabsorb more water

↓

Less urine is produced

↓

Thirst increases

↓

Water intake increases

↓

Blood volume increases

↓

Blood pressure returns toward normal

↓

Osmolarity returns to normal

what happens in a hypervolemic state to restore balance?

Hypervolemia (too much water)

Blood volume ↑

↓

ECF osmolarity ↓

↓

ADH decreases

↓

Kidneys reabsorb less water

↓

More water is excreted

↓

Urine volume increases

↓

Blood pressure decreases toward normal

↓

Osmolarity returns to normal

functions that occur when magnesium is low

Low magnesium causes:

• Increased PTH release

• Increased bone resorption

• Increased intestinal magnesium absorption

• Decreased urinary magnesium excretion

Purpose:

Raise plasma magnesium back to normal.

deficiency of magnesium – what happens during it, how should it be treated, etc. Same for

potassium, and sodium. Toxicity for each if relevant

deficiency of magnesium

hypomagnesemia

deficiency of magnesium Causes

• Poor intake

• Alcoholism

• Malabsorption

• Diuretics

• PPIs

• Chemotherapy

• Burns

• Uncontrolled diabetes

deficiency of magnesium Symptoms

• Muscle cramps

• Weakness

• Tremors

• Heart arrhythmias

• Neurological problems

deficiency of magnesium Treatment

• Magnesium supplements

• Correct underlying cause

• Increase magnesium-rich foods

magnesium toxicity

Hypermagnesemia

Hypermagnesemia

• Causes:

  • Supplements

  • Antacids/laxatives

  • Impaired kidney function

• Symptoms:

  • Diarrhea

  • Nausea/vomiting

  • Low blood pressure

  • Muscle weakness

  • Loss of reflexes

  • Flushing

  • Slurred speech

  • Muscle paralysis

  • Cardiac/respiratory failure (>15 mg/dL)

• UL = 350 mg/day (from supplements/nonfood sources)

Hyperkalemia

• Usually from:

  • Renal failure

  • High-dose supplements

• Symptoms:

  • Heart arrhythmias

  • Muscle weakness

  • Twitching

  • Cramping

  • Ascending paralysis

• Both hypo- and hyperkalemia can be potentially deadly.

Hypokalemia Causes

• Vomiting

• Diarrhea

• Large fluid losses

• Diuretics

• Kidney disease

• Magnesium deficiency, which increases urinary potassium loss

Hypokalemia What happens

• Cells become less excitable.

• Nerve and muscle function decreases.

• Heart rhythm can become abnormal.

Symptoms:

• Muscle weakness

• Lethargy

• Muscle cramps

• Heart arrhythmias

• Possible death

Hypokalemia Treatment

• Potassium supplements under medical supervision

• Increase potassium-rich foods

• Correct magnesium deficiency if present

• Treat vomiting, diarrhea, or the other underlying cause

Hypokalemia

Causes:

• Vomiting

• Diarrhea

• Large fluid losses

• Diuretics

• Kidney disease

• Magnesium deficiency, which increases urinary potassium loss

What happens:

• Cells become less excitable.

• Nerve and muscle function decreases.

• Heart rhythm can become abnormal.

Symptoms:

• Muscle weakness

• Lethargy

• Muscle cramps

• Heart arrhythmias

• Possible death

Treatment:

• Potassium supplements under medical supervision

• Increase potassium-rich foods

• Correct magnesium deficiency if present

• Treat vomiting, diarrhea, or the other underlying cause.

Hyponatremia Causes

• Overhydration

• Excess ADH

• Vomiting or diarrhea with fluid replacement that lacks electrolytes

• Heavy sweating followed by drinking only water

• Some kidney, heart, or hormonal disorders

Hyponatremia What happens:

• ECF becomes hypotonic.

• Water moves into cells.

• Cells swell.

• Brain-cell swelling is the major danger.

Symptoms:

• Headache

• Nausea

• Confusion

• Weakness

• Muscle cramps

• Seizures

• Coma in severe cases

Hyponatremia Treatment

• Restrict water when caused by overhydration

• Replace sodium carefully when sodium has been lost

• Treat the underlying cause

• Severe cases may require carefully controlled IV saline

Sodium must be corrected slowly because correcting it too rapidly can cause serious neurological injury. The PowerPoint describes hyponatremia as water gain without solutes, producing low ECF osmolarity and cell swelling

Hypernatremia

• Loss of water without solutes

• High serum sodium

• Hypertonic ECF

• Dehydration

So for sodium, your professor focuses on hypernatremia (too much sodium in the blood due to water loss), not "sodium toxicity" from excessive intake.

What are the functions of phosphorus and what is it required for

Bone mineralization

Forms calcium phosphate in bone.

---

ATP production

Stores and transfers energy.

---

DNA and RNA

Forms the phosphate backbone.

---

Cell membranes

Part of phospholipids.

---

Second messenger systems

Part of:

• ATP

• cAMP

• GTP

---

Protein phosphorylation

Activates many enzymes.

---

Acid-base balance

Acts as an intracellular buffer.

---

Oxygen delivery

Part of 2,3-DPG, helping release oxygen from hemoglobin.

---

Vitamins

Needed to activate:

• Thiamin (TPP)

• Vitamin B6 (PLP)

what happens when serum phosphorus levels increase-what regulates levels and how?

Sequence

Serum phosphorus ↑

↓

FGF23 released

↓

Kidney:

• ↓ 1α-hydroxylase

• ↑ 24-hydroxylase

↓

Calcitriol decreases

↓

Kidney:

↓ NaPi2a

↓

↓ NaPi2c

↓

Less phosphate reabsorbed

↓

More phosphate lost in urine

↓

Intestine:

↓

Fewer NaPi2b transporters

↓

Less phosphorus absorbed

↓

Serum phosphorus returns to normal.

what regulates phosphorus levels?

• FGF23 (main regulator)

• Calcitriol

• PTH

Requirements for phosphorus absorption

Requirements

• Phosphorus must be in the inorganic phosphate (Pi) form.

• Bound phosphorus must be released by digestive enzymes.

• Most absorption occurs in the jejunum.

• About 50–80% is absorbed.

Digestive enzymes required

• Phospholipase C (zinc dependent)

  • Releases phosphate from phospholipids.

• Alkaline phosphatase (zinc dependent)

  • Releases phosphate from many organic molecules at the brush border.

what increases phosphourous absorbtion

• Calcitriol (Vitamin D)

• Animal foods

• Low phosphorus intake (more NaPi2b transporters)

What decreases phosphorus absorption?

• Calcium

• Magnesium

• Iron

• Aluminum

• Antacids

• High-dose niacin

• Phytates

• Zinc deficiency

• Lack of calcitriol

Foods that decrease phosphorous absorption

High phytate foods:

• Whole grains

• Wheat

• Corn

• Rice

• Legumes

Humans do not have phytase, so phosphorus cannot be released efficiently.

Two absorption mechanisms of phosphorous

1. Passive diffusion (main mechanism)

• Most phosphorus is absorbed this way.

• Occurs throughout the small intestine.

---

2. Active transport

Uses the NaPi2b cotransporter.

Occurs mostly when phosphorus intake is low.

Calcitriol increases the number of NaPi2b transporters.

Calcium absorption mechanisms from the gut into the enterocyte and then from there into the blood

Intracellular (Transcellular) absorption

Main pathway when calcium intake is low to moderate.

Step 1

Calcium enters the enterocyte through TRPV6.

↓

Step 2

Calbindin D9k carries calcium across the cell.

↓

Step 3

Calcium leaves the cell by:

• PMCA1b (ATP pump)
  OR

• NCX1 (Na+/Ca²⁺ exchanger)

↓

Step 4

Calcium enters the blood.

decrease calcium absorbtion

• Oxalates

• Phytates

• Fiber

• Rapid GI movement

• High-fat diet

• Fat malabsorption

• Low stomach acid

• Aging

• Excess phosphorus

• Excess magnesium

• Excess zinc

• FGF23

increase calcium absorbtion

• Vitamin D (calcitriol)

• Acidic stomach

• Lactose

• Sugar alcohols

• Protein eaten with calcium

• Pregnancy

• Lactation

• Childhood growth

• Spreading calcium intake throughout the day

Paracellular absorption

(Between cells)

Occurs when calcium intake is high.

Calcium moves between enterocytes, not through them

Solvent drag

1. Na⁺/K⁺ ATPase pumps sodium out.

2. Water follows sodium.

3. Water carries calcium between cells.

4. Calcium enters the blood.

No carrier proteins are required

Colon absorption

Gut bacteria ferment fiber.

↓

Release calcium that was bound to fiber.

↓

About 4–10% more calcium can be absorbed

What foods can influence calcium absorption positive

• Dairy products

• Foods with vitamin D

• Milk (contains lactose)

What foods can influence calcium absorption negative

High oxalate foods:

• Spinach

• Swiss chard

• Rhubarb

• Beets

• Celery

High phytate foods:

• Whole grains

• Nuts

• Seeds

• Legumes

These bind calcium so it cannot be absorbed.

High-yield things to memorize

• Provitamin: 7-dehydrocholesterol

• Skin form: Cholecalciferol (Vitamin D3)

• Liver form: 25-OH Vitamin D (Calcidiol)

• Active form: 1,25-(OH)₂ Vitamin D (Calcitriol)

• Storage/blood form measured: 25-OH Vitamin D

• Liver enzyme: 25-hydroxylase

• Kidney enzyme: 1α-hydroxylase

• Breakdown enzyme: 24-hydroxylase

• Transport protein: VDBP

• Hormone that increases calcitriol: PTH

• Hormone that decreases calcitriol: FGF23

• Main job: Increase calcium and phosphorus absorption.

understand slide 12 and 13

what the regulation steps are and response. For example, if I say blood calcium levels drops what happens next, then you need to know what is released and what happens to bring blood calcium levels back up (hormones, other organs involved, etc). Combine the information across the vit D and calcium lecture to make sure you know it all. Draw out pictures or the sequence of events multiple times from memory to make sure you have it all.

When blood calcium drops

1. Blood calcium ↓

2. Parathyroid glands release PTH

3. Kidney:

   • ↑ 1α-hydroxylase

   • ↑ Calcitriol production

4. Intestine:

   • ↑ Calcium absorption

5. Kidney:

   • ↑ Calcium reabsorption

6. Bone:

   • ↑ Bone resorption

7. Blood calcium returns to normal.

When blood calcium rises

1. Blood calcium ↑

2. PTH decreases

3. Less calcitriol made

4. Less intestinal calcium absorption

5. Less bone resorption

6. Blood calcium falls toward normal.

Regulation by FGF23

When phosphorus is high:

• Osteocytes release FGF23

• ↓ 1α-hydroxylase

• ↑ 24-hydroxylase

• ↓ Calcitriol

• ↓ Intestinal phosphorus absorption

• ↑ Urinary phosphorus excretion

know the steps of vitamin D activation in the body following its absorption-what form moves between the different organs? And which organs? Where or when is it/can it be hydroxylated? what enzymes are involved?

Step 1
Dietary Vitamin D or skin Vitamin D enters blood.

Step 2
Vitamin D travels bound to Vitamin D Binding Protein (VDBP).

Step 3
Liver:

• 25-hydroxylase

• Makes 25-OH Vitamin D (Calcidiol).

Step 4
25-OH Vitamin D travels in blood on VDBP.

Step 5
Kidney:

• 1α-hydroxylase

• Makes Calcitriol (1,25-(OH)₂D).

Other tissues

• Some tissues also contain 25-hydroxylase and 1-hydroxylase for local activation.

vitamin D conversion between different intermediates and when it goes to one form or another. Sample slides to review include #6, #7, 10, 14. You don’t need to know the structures but the intermediate names if they are important to things we discussed in the lecture or its breakdown and removal from the body.

Vitamin D pathway:

1. 7-dehydrocholesterol (skin)

2. UVB light → Previtamin D3

3. Thermal isomerization (hours to days) → Vitamin D3 (cholecalciferol)

4. Blood (bound to Vitamin D Binding Protein (VDBP))

5. Liver:

   • 25-hydroxylase (CYP27A1) adds OH

   • Makes 25-OH Vitamin D (Calcidiol)

6. Kidney:

   • 1α-hydroxylase adds second OH

   • Makes 1,25-(OH)₂ Vitamin D (Calcitriol) = active form

Breakdown

• 24-hydroxylase converts calcitriol into inactive forms:

  • 24,25-(OH)₂D

  • 1,24,25-(OH)₃D

• These are broken down and removed from the body