GLUT Receptors and Aquaporins ( One liners for DNB)

Aquaporin Channels-

Aquaporin 0 – lens (fluid balance)

Aquaporin 1 – RBCs (osmotic protection)
PCT (urine concentration)
Ciliary epithelium of eye (aqueous humor production)
Choroid plexus (CSF production)
Alveolar epithelial cell (alveolar hydration)

Aquaporin 2 – Collecting duct (ADH activity)

Aquaporin 3 – Collecting duct (water reabsorption into blood)
tracheal epithelial cells

Aquaporin 4 – collecting duct duct (water reabsortion)
Ependymal cells (CSF balance)
Hypothalamus (osmotic function)
Bronchial epithelium

Aquaporin 5 – salivary gland (saliva production)
Lacrimal gland (tear production)

Aquaporin 6 – kidney

Aquaporin 7 – fat cells (glycerol transport out of adipocytes)
Testis n sperm

Aquaporin 8 – testis, pancreas, liver

Aquaporin 9 – adipose tissue, areas lacking BBB

Aquaporin 3, 7 n 9 are aquaglyceroporins

Mutation in aquaporin 2 is asso. with Hereditary Nephrogenic Diabetes Insipidus

Deficiency of aquaporin4 – Neuromyelitis optica (Devic’s dis), it resembles with multiple sclerosis

Deficiency of aquaporin 7 and 9 is associated with Obesity.

GLUT Receptors-

GLUT 1 – RBCs (other sites are placenta,brain, kidney, colon)

GLUT 2 – Liver (other sites are pancreatic beta cell, kidney, small intestine)

GLUT 3 – Brain, testis

GLUT 4 – Adipose tissue, Skeletal muscle, Heart muscle

GLUT 5 – Intestine, testis, kidney, sperm (for fructose)

GLUT 6 – Leukocyte, spleen

Phosphodiesterase Enzyme Inhibitors-

PDE1 inhibitor: Vinpocetine

PDE2inhibitor: EHNA

PDE3 inhibitor: Enoximone,milrinone,Amrinone

PDE4 inhibitor: Ibudilast,pentoxiffyline,cilomilast,

PDE5 inhibitor: Sildenafil, tadalafil and vardenafil,

NONSELECTIVE: Theophyllins

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Concept of Delta Gap in Acid-Base Balance

To understand if a patient has both increased anion gap acidosis and non-gap acidosis at the same time or metabolic acidosis + metabolic alkalosis at the same time, you will need to know the concept of “Delta Gap

The Delta Gap = Measured SAG – Normal SAG

Logically, if the serum bicarbonate (Hco3-) falls more than the change in the anion gap,then a patient has both non-gap+increased gap acidosis.

If the serum bicarbonate falls less than the change in the anion gap, then the patient has mixed disorder – metabolic acidosis + metabolic alkalosis.

For example, if the anion gap is 20 –> you can say the change in the anion gap is 8 ( because normal anion gap is 12. ) In this scenario let us say if the MCQ gave serum Hco3- as 10, drop in the serum bicarb here is 14 ( remember, for calculation normal serum bicarb is taken as 24. so, if it is 10 now, the drop in bicarb is obviously, 14). –> this means when your anion gap has increased by 8 your bicarb has fallen more than 8 i.e; by 14….that means some other factor apart from the factor responsible for increased gap acidosis is also contributing to acidosis here! – this suggests co-existing increased anion-gap+normal-gap acidosis .

A classic example is diarrhea with shock – where diarrhea causes non gap acidosis but shock can lead to lactic acidosis which increases the gap – so, things can co-exist!

To understand if your patient has a mixed disorder of metabolic acidosis + respiratory acidosis or metabolic acidosis + respiratory alkalosis, you will need to be familiar with Winter’s formula. 

Winter;s formula :
Expected pCo2 = {1.5(Hco3-) +8} +/-2

If your patient has metabolic acidosis, you expect him to breathe fast and wash out the Co2 so as to maintain the pH in normal limits …this is called “Compensation”. Compensation brings the serum pH towards the normal but never makes it completely normal – so, if you are seeing a normal pH in a metabolic acidosis , you can right away say that you are dealing with a Mixed disorder rather than a compensation alone.
The expected Pco2 in the above formula is the one that is expected as a comprnsation if your patient has low bicarbonate or metabolic acidosis. You need to compare this expected Pco2 with the real value of Pco2 obtained on the arterial blood gases ( measured Pco2).

Pearls for answering questions on Mixed Disorders:
A) If measured Pco2 is lower than the expected Pco2, that means your patient is washing out more C02 than expected —meaning, he has respiratory alkalosis co-existent with metabolic acidosis ( one example of such mixed disorder is Salicylate toxicity) .

B) If measured Pco2 is higher than expected Pco2, that means your patient is retaining Co2 which means he has a co-existent Respiratory acidosis along with metabolic acidosis ( eg: Cardiac arrest can cause such mixed acidosis because reduced respiratory drive causes CO2 retention leading to respiratory acidosis where as shock because of cardiac arrest causes lactic acidosis which is metabolic acidosis).

Eg: If Hc03 – is 16, the expected PCo2 as per Winter;s formula should range between 30 to 34 ( see the above formula). However, let us say your patients Pco2 on the arterial blood gas is 20 –> you can call this metabolic acidosis + respiratory alkalosis. eg : Salicylate Toxicity

If Hc03 – is 16, the expected PCo2 as per Winter;s formula should range between 30 to 34 ( see the above formula). However, let us say your patients Pco2 on the arterial blood gas is 44 –> you can call this metabolic acidosis + respiratory acidosis. eg : Cardiac arrest

LAWS IN PHYSIOLOGY 1

1 . WEBER -FECHNER LAW : Magnitude of sensation felt by sensory receptors is proportional to log of intensity of the stimulus.

2. LAW OF SPECIFIC ENERGIES : When a nerve pathway from a particular sense organ is activated the sensation evoked is that for which receptor is specialised no matter were along the pathway the activity is initiated . eg if a sensory nerve from pacinian corpuscle in hand is activated at elbow by compression then the sensation evoked is touch .

3. LAW OF PROJECTION : No matter were a particular sensory pathway is activated along its course to cortex, the concious sensation produced is reffered to location of receptor.

4. BELL-MAGENDIE LAW : The principle that in spinal cord the dorsal roots are sensory and the ventral roots are motor is known as bell-magendie law.

5. SIGGARD-ANDERSON CURVE NOMOGRAM : it is used to plot acid base charecteristics of arterial blood were Pco2 is plotted on a log scale on vertical axis and pH on a horizontal axis.

6. FICKS LAW OF DIFFUSION : The magnitude of the diffusing tendency from one region to another is directly proportional to the cross section area across which diffusion is taking place and the concentration gradient or chemical gradient , which is the difference concentration of the diffusing substance divided by thickness of the boundary

j = -DA ( CHANGE IN CONC/ THICKNESS)

Q] Ficks law of diffusion explains ….[AIIMS MAY 2013]

[A] Active diffusion along concentration gradient

[B] Passive diffusion along concentration gradient

[c] both of these

[d] none of these 

ANS = [b] ficks law explains net rate of passive diffusion along concentration gradient

7. DONNAN EFFECT : When an ion on one side of membrane cannot diffuse through the membrane , the distribution of other ions to which the membrane is permeable is affected in a predictable way.

8. GIBBS-DONNAN EQUATION : it is a equation showing that in presence of non diffusible ion , the diffusible ions distribute themselves so that at equillibrium their concentration is equal .

9. NERNST EQUATION : Is used to calculate the electric difference across the membrane.

ESOPHAGUS PART 2 : ACHALASIA TREATMENT AND OTHER MOTILITY DISORDERS

Q1] HELLERS OPERATION IS DONE FOR …[AIIMS NOV 93]

A] Achalasia cardia

B] Pyloric stenosis

C] Peptic ulcer

D] Ca Esophagus

ans =[a]

Q2] A young female presents with dysphagia for the past 2 years. she also complains of intermittent chest pain . Barium shallow shows dialation of esophagus with narrowing of the distal esophagus. the treatment of choice is ..[AIIMS MAY 2012]

A] Hellers cardiomyotomy

B] Esophagectomy

C] Coronary angiography

D] Proton pump inhibitor

ANS = [A] Hellers cardiomyotomy as the description fits the diagonosis of achalasia cardia [ see part 1 of this topic for diagonostic flochart] .Treatment of choice is laproscopic cardiomyotomy ( heller myotomy) { ref schwartz 9th ed page 859} .See the figure provided below

Image

so TOC of ACHALLASIA IS = HELLAR MYOTOMY [ SCHWARTZ 9ed page 859]

a/c to medscape = hellar myotomy + partial fundoplication is appropriate treatment[ as it decresses chances of reflux also ]

Q3] DIFFUSE ESOPHAGEAL SPASM IS BEST DIAGONOSED BY [AI 2008]

ANS = MANOMETRY [ see the figure provided below to understand manometric criterias for diagonosis of DES]

Q4] CORKSCREW ESOPHAGUS IS SEEN IN WHICH OF FOLLOWING CONDITIONS[ AI 2002]..

ANS = DIFFUSE ESOPHAGEAL SPASM [ see fig below]

Image

NOW LETS UNDERSTAND DIFFERENCE BETWEEN CORKSCREW AND NUTCRACKER ESOPHAGUS:

In nutcracker peristaltic sequence is normal and peristaltic amplitude and duration is increased in distal esophageal body[ see the figure below]

Image

Q5] MOST APPROPRIATE INITIAL TREATMENT OF NUTCRACKER ESOPHAGUS IS …

A] PPI

B] Calcium channel blocker

C] Nitroglycerin

D] Dialation

ans = [a] PPI . Treatment should be aimed at GERD as it is unclear that chest pain in nutcracker eso is due to acid reflux or intraluminal hypertension [ schwartz 9ed page852]

NOTE : ? IS HYPERTENSIVE LES ; Elevated LES pressure more than or equal to 26 mmHg with normal peristalsis in eso body and normal LES relaxation.

ESOPHAGUS : PART 1 ( LES , DYSPHAGIA AND ACHALASIA)

LOWER ESOPHAGEAL SPHINCTER = LES

The tone of LES is under neural control. Vagal endings by releasing acetylcholine cause contraction of LES and the vagal nerve endings on interneurons release NO and VIP which cause relaxation of LES. NOTE: in achalasia myenteric plexus is deficient at LES so release of NO and VIP is defective.

Q1] For normal functioning of LES all of the followig factors are important except….

a] length of intrabdominal esophagus

b] total length of LES

c] Width of diaphragmatic hiatus

d] resting tone in LES

ANS =[C] Width of diaphragmatic hiatus is not important ( see figure below)

Image

Image

Q2] Which of manometric finding is indicative of incompetent LES..?

A] resting LES tone< 25 mm hg

B] Total LES length < 2 cm

C] Intra-abdominal  length of LES < 3cm

D] Average LES pressure < 20 mm Hg

ANS =[B] TOTAL LES LENGTH < 2CM IS INDICATIVE OF INCOMPETENT LES

NOTE 1. Alpha adrenergic agents or Beta blockers , gastrin , motilin , bombesin , enkephalin and substance P   INCREASE LES tone.

NOTE 2. Cholecystokinin , estrogen , progesterone , glucagon , secretin and somatostatin DECREASE LES tone.

NOW LET US UNDERSTAND NORMAL MANOMETRY : Probes are applied at different locations within esophagus to record pressure hanges . Normally peristaltic wave travel down the esophagus and when the food bolus reaches LES then LES relaxes and allows the food to enter stomach. See the indicative manometric curve in figure below:

Image

Q] NON PROGRESSIVE CONTRACTION  OF ESOPHAGUS ARE… [AI 2009]

A] PRIMARY [B] SECONDARY  [C] TERTIARY  [D] QUATERNARY

ANS = [C] TERTIARY (see figure below)

Image

NOW LETS LEARN DIFFERENT CAUSES OF DYSPHAGIA THROUGH FLOW CHARTS:

Image

Image

Q3] INTERMITTENT DYSPHAGIA IS CAUSED BY …[PGI JUNE 2004]

A] Stricture

B] Achalasia cardia

C] Pharyngeal diverticulum

D] Diffuse esophageal spasm

ANS = [C] and [D] SEE FIGURE ABOVE

CAUSES OF INTERMITTENT DYSPHAGIA [A] Diffuse esophageal spasm [B] Zenkers diverticulum [C] Lower esophageal ring / schzatki ring.

Q4] Investigation of choice of dysphagia to solids only is .[PGI DEC 03 JUNE 00]

ANS = AS DYSPHAGIA TO SOLID signifies MECHANICAL OBSTRUCTION so investigation of choice in this case is = endoscopy.

NOTE: Barium is better for evaluation of motility disorder and zenkers diverticulum as compared to endoscopic evaluation. In case of motility disorders the diagonosis is confirmed by manometry so Investigation of choice is MANOMETRY.

ACHALASIA:

Q5] The initial pathological change that leads to clinical findings of achalasia is..

a] Increased reting LES tone

b] aperistalsis of esophageal body

c] hypertension of body of esophagus

d] failure of LES relaxation

ANS = [A] HYPERTENSIVE LES/ INCREASED LES RESTING TONE is primary pathology in ACHALASIA . it is bcoz of dysfunction of inhibitory neurons releasing NO and VIP so that acetylcholine releasing  excitatory vagal fibres take upper  hand.( see the figure below)

Image

Q6] IN ACHALASIA TRUE IS … [PGI JUNE 2000]

a] pressure at distal end increased with no peristalsis

b] low pressure at LES with no peristalsis

c] pressure > 50 mm Hg with peristalsis

d] pressure at distal end increased with normal relaxation

ANS = [A] PRESSURE AT DISTAL END INCREASED WITH NO PERISTALSIS.

NOTE : CHAGAS DISEASE = AMERICAN TRYPANOSOMIASIS IS CAUSED BY Trypanosoma cruzi and transmitted among mammalian hosts by hematophagus reduvid bugs. Symptomatic chronic disease = CARDIAC DISEASE { arrythmia (Mostly Right Bundle Branch Block) , dialated cardiomyopathy , throembolism} + MEGAESOPHAGUS( So chagas disease can lead to achalasia) + MEGACOLON.

NEXT : ESOPHAGUS  PART 2 ( ACHALASIA TREATMENT AND OTHER MOTILITY DISORDERS OF ESOPHAGUS)

References [1] ganong review of medical physiology 23ed pg 471

[2] schwartz `s principles of surgery  9ed page 812, 816 , 828, 851

[3] current diagonosis and treatment in gastroenterology 2nd ed page 288

[4] harrison 17 ed 1300 ,1847