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QUICK TOPIC INDEX

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PHYSIOLOGY PAPER 1 - COMPLETE REVISION GUIDE

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1. IRON DEFICIENCY ANEMIA - Clinical Case

• Dietary Fe3+ reduced to Fe2+ by duodenal cytochrome B, absorbed via DMT-1 at apical membrane of duodenal enterocytes
• Ferroportin transports iron from enterocyte to plasma at basolateral membrane
• Hepcidin (liver peptide) negatively regulates ferroportin - high iron stores → high hepcidin → blocks ferroportin → reduces absorption
• Transferrin carries iron in plasma (~33% saturated normally); TIBC = 300-350 µg/dL

1. Storage depletion: serum ferritin falls, bone marrow iron disappears
2. Transport iron deficiency: serum iron falls, TIBC rises, transferrin saturation <15%
3. Iron-deficiency anemia: microcytic hypochromic anemia, low MCV, low MCH

• Low serum ferritin (best indicator of iron stores)
• Low serum iron, high TIBC, low transferrin saturation
• Microcytic hypochromic RBCs; low MCV (<80 fL)
• Low reticulocyte count

• Increased demand: pregnancy, growth spurts
• Decreased intake: poor diet, malabsorption (celiac disease)
• Chronic blood loss: menstruation, GI bleed (peptic ulcer, colorectal cancer)

• General: fatigue, weakness, headache, pallor
• Cardiovascular: palpitations, exertional dyspnea, tachycardia
• Nails: koilonychia (spoon nails)
• Mouth: angular stomatitis, glossitis
• Pica (craving for ice, clay, dirt)
• Plummer-Vinson syndrome (IDA + post-cricoid dysphagia + esophageal web)

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2. INNERVATION OF BLADDER AND MICTURITION REFLEX

• Detrusor muscle (smooth muscle) - forms wall
• Internal urethral sphincter (smooth, involuntary) - at bladder neck
• External urethral sphincter (skeletal, voluntary) - in urogenital diaphragm

1. Bladder fills (400-500 mL) → stretch receptors in detrusor wall fire
2. Afferent signals via pelvic nerve → sacral micturition centre (S2-S4)
3. Efferent signals via parasympathetics → detrusor contraction
4. Simultaneously, sympathetic inhibition → internal sphincter relaxes
5. Higher centres (pontine micturition centre, frontal cortex) allow voluntary initiation or inhibition
6. Voiding: voluntary relaxation of external sphincter → urine expelled

• Above pontine centre: loss of voluntary control, reflex micturition intact (automatic/uninhibited bladder)
• Below S2-S4: flaccid areflexic bladder (overflow incontinence)

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3. CAISSON DISEASE (Decompression Sickness / "The Bends") - Clinical Case

• At depth, increased ambient pressure → nitrogen (inert gas) dissolves in blood/tissues (Henry's law: gas solubility ∝ pressure)
• Rapid ascent = rapid decompression → nitrogen supersaturated → comes out of solution → forms gas bubbles in blood and tissues
• Bubbles obstruct vessels → local ischemia → direct tissue damage

• Nitrogen bubbles trapped in spinal vessels → ischemia mainly in upper thoracic cord white matter (posterior > lateral > anterior columns)
• Can produce near-complete transverse myelopathy: spasticity, numbness, lower limb weakness

• Immediate: Recompression in hyperbaric oxygen chamber (100% O2 at 2.8 atm) - re-dissolves nitrogen bubbles
• Later: antispasticity drugs, physiotherapy for residual deficits

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4. CELL-MEDIATED IMMUNITY (CMI)

• Recognize antigen on MHC Class II on APCs (dendritic cells, macrophages)
• Secrete IFN-γ, IL-2, TNF-β
• Activate macrophages to kill intracellular organisms (e.g., Mycobacterium tuberculosis)

• Recognize antigen on MHC Class I on infected cells
• Kill infected cells by releasing perforin (pores in membrane) + granzymes (serine proteases → caspase cascade → apoptosis)
• Essential for viral infections and tumor surveillance

1. TCR binds antigen-MHC complex
2. Co-stimulatory signals: CD28 (T cell) + B7 (APC)
3. Cytokines (IL-2 → clonal expansion)

• Tuberculin (Mantoux) test - Type IV hypersensitivity
• Contact dermatitis
• Graft rejection
• Tumor immunity
• Impaired CMI: HIV/AIDS (CD4+ depletion), DiGeorge syndrome (no thymus)

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5. HYPOVOLEMIC SHOCK - Clinical Case

1. Baroreceptor reflex: Low BP → sympathetic activation → tachycardia, vasoconstriction
2. RAAS: Reduced renal perfusion → renin → angiotensin II → aldosterone → Na+/water retention
3. ADH (vasopressin): From posterior pituitary → water retention
4. Transcapillary refill: Fluid moves from interstitial → plasma
5. Erythropoietin: Increased RBC production (delayed response)

• IV large-bore access; crystalloid (normal saline/Ringer's lactate) for Class I-II
• Blood transfusion for Class III-IV
• Stop source of bleeding (surgical intervention)
• Massive transfusion protocol: 1:1:1 ratio (pRBC : FFP : Platelets)

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6. PERIPHERAL CHEMORECEPTORS

• Carotid bodies: at bifurcation of common carotid arteries (most important)
• Aortic bodies: above and below aortic arch

• Carotid bodies → CN IX (glossopharyngeal) → Dorsal Respiratory Group (DRG) in medulla
• Aortic bodies → CN X (vagus) → DRG

1. Decreased arterial PO2 (hypoxia): Most important function. Insensitive until PaO2 <60 mmHg. Below 60 mmHg → steep, dramatic increase in ventilation (hypoxic ventilatory response). Between 100-60 mmHg, breathing is virtually unchanged.
2. Increased arterial PCO2: Less important than central chemoreceptors' response to CO2.
3. Decreased arterial pH: Direct effect, independent of PCO2. Only carotid bodies (not aortic) respond to pH. Drives respiratory compensation for metabolic acidosis.

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7. ACTIVE TRANSPORT

Primary Active Transport

• Na+-K+ ATPase: Pumps 3 Na+ out + 2 K+ in per ATP hydrolyzed. Present in all cell membranes. Maintains RMP and cell volume. On basolateral side of epithelial cells - drives all secondary transport. Electrogenic (net 1 positive charge out per cycle).
• H+ ATPase, H+-K+ ATPase (gastric parietal cells - acid secretion; renal tubule)
• Ca2+ ATPase (sarcoplasmic reticulum, plasma membrane)

Secondary Active Transport

• Cotransport (symport): Solute moves in same direction as Na+. Examples: Na+-glucose (SGLT) in proximal tubule + intestine; Na+-amino acid cotransport
• Counter-transport (antiport): Solute moves in opposite direction to Na+. Examples: Na+-H+ exchanger (NHE) in proximal tubule; Na+-Ca2+ exchanger

• Transcellular: through the cell via membrane transporters
• Paracellular: between cells through tight junctions (claudins, occludins regulate selectivity)

• SGLT2 inhibitors (dapagliflozin): block Na+-glucose cotransport in proximal tubule → glucosuria → used in type 2 diabetes + heart failure
• Digitalis: inhibits Na+-K+ ATPase → ↑ intracellular Na+ → inhibits Na+-Ca2+ exchanger → ↑ intracellular Ca2+ → positive inotropic effect

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8. PEPTIC ULCER - Clinical Case

• Aggressive factors: HCl, pepsin, H. pylori, NSAIDs, bile reflux, smoking
• Protective factors: Mucus-bicarbonate barrier, prostaglandins (PGE2/PGI2), mucosal blood flow, tight junctions, Brunner glands, pancreatic bicarbonate

• Gram-negative, microaerophilic, urease-producing bacterium
• Urease splits urea → NH3 + CO2 → NH3 buffers acid → allows survival in stomach
• Causes mucosal inflammation → disrupts mucous barrier → H+ penetration → ulceration
• Causes >95% of duodenal ulcers and ~75% of gastric ulcers

• Inhibit COX-1 → reduced prostaglandin synthesis → reduced mucus + bicarbonate secretion + reduced mucosal blood flow → impaired mucosal defense

• Epigastric pain: burning/gnawing
• Duodenal ulcer: Pain improves with food, worsens 2-3 hours post meal, nocturnal pain
• Gastric ulcer: Pain worsened by food, associated weight loss
• Nausea, vomiting, belching

• H. pylori eradication: Triple therapy (PPI + amoxicillin + clarithromycin × 14 days)
• PPIs (proton pump inhibitors)
• Stop NSAIDs; use COX-2 selective agents if unavoidable + PPI cover

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9. SINO-AORTIC REFLEX / BARORECEPTORS

• Carotid sinus (most important): at bifurcation of common carotid artery
• Aortic arch

• Carotid sinus → Hering's nerve (branch of CN IX) → NTS (nucleus tractus solitarius) in medulla
• Aortic arch → CN X (vagus) → NTS

• Rapidly adapting (reset in chronic hypertension - "baroreceptor resetting")
• Most sensitive between 75-150 mmHg MAP
• Respond to rate of pressure change, not just pressure level

• Carotid sinus massage: Slows HR → used in diagnosis/termination of SVT
• Carotid sinus hypersensitivity: Exaggerated reflex → syncope
• Postural hypotension: Failure of baroreceptor compensation (autonomic neuropathy - diabetes, Parkinson's)
• Valsalva maneuver: Tests baroreceptor integrity (4 phases)
• Bainbridge reflex: Right atrial stretch → HR increase (matches cardiac output to venous return)

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10. HEMOLYTIC DISEASE OF THE NEWBORN (HDN) - Clinical Case

1. Rh-negative mother carries Rh-positive fetus (D antigen inherited from father)
2. At first delivery: fetal RBCs enter maternal circulation (fetomaternal hemorrhage) → mother sensitized → forms anti-D IgG antibodies
3. In 2nd (or subsequent) Rh+ pregnancy: IgG anti-D crosses placenta into fetus
4. IgG coats fetal Rh+ RBCs → agglutination and hemolysis → macrophages phagocytose RBCs

• Anemia: Fetus anemic; liver and spleen enlarge (extramedullary erythropoiesis) → hepatosplenomegaly; nucleated RBCs (erythroblasts) in circulation → erythroblastosis fetalis
• Jaundice/Kernicterus: Excess bilirubin (unconjugated) → crosses blood-brain barrier → kernicterus - damage to basal ganglia/brain stem → deafness, athetoid cerebral palsy, mental disability
• Hydrops fetalis: Severe hemolysis → heart failure → generalized edema, ascites, pleural effusions → fetal death

• 1st Rh+ baby: usually no problem (sensitization occurs)
• 2nd Rh+ baby: ~3% affected
• 3rd and beyond: progressively increasing

• Exchange transfusion with Rh-negative blood (replaces Rh+ cells, removes bilirubin and antibodies)
• Phototherapy: Converts unconjugated bilirubin → water-soluble isomer → excreted in urine/bile
• Intrauterine transfusion for severe fetal anemia detected prenatally

• Anti-D immunoglobulin (Rh immunoglobulin): Given to Rh-negative mothers:
  • At 28-30 weeks gestation
  • Within 72 hours of delivery, miscarriage, or any invasive procedure
• Mechanism: Anti-D IgG destroys fetal Rh+ cells entering maternal circulation before sensitization can occur

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11. COPD + OXYGEN-DISSOCIATION CURVE + OXYGEN TRANSPORT + OXYGEN THERAPY

A. Chronic Obstructive Pulmonary Disease (COPD)

• Chronic bronchitis: Productive cough >3 months/year for ≥2 consecutive years
• Emphysema: Destruction of alveolar walls distal to terminal bronchiole

• Cigarette smoke → chronic inflammation → neutrophils/macrophages → proteases (elastase) destroy alveolar walls (emphysema) + mucus hypersecretion (bronchitis)
• Loss of elastic recoil → airway collapse on expiration → air trapping → hyperinflation
• V/Q mismatch → hypoxia → eventually hypercapnia (Type II respiratory failure)

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B. Oxygen-Dissociation Curve (ODC)

• PaO2 = 100 mmHg (arterial blood) → Hb saturation ~97-98%
• PaO2 = 40 mmHg (venous blood) → Hb saturation ~75%
• P50 = 26.5 mmHg (PO2 at which Hb is 50% saturated; index of O2 affinity)

• Flat upper portion (>60 mmHg): O2 loading in lungs protected even if PaO2 falls moderately
• Steep lower portion (20-60 mmHg): Small drop in tissue PO2 → large O2 unloading at tissues → efficient delivery

• ↑ PCO2 (Bohr effect)
• ↑ Temperature
• ↓ pH (acidosis)
• ↑ 2,3-DPG (chronic anemia, high altitude, COPD)

• ↓ PCO2, ↓ Temperature, ↑ pH (alkalosis)
• Fetal Hb (HbF)
• COHb (carbon monoxide poisoning) - Hb binds CO ~240× more avidly than O2
• Methemoglobin

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C. Physiological Mechanisms of Oxygen Transport

• 0.003 mL O2/dL per mmHg PaO2
• At PaO2 100 mmHg: only ~0.3 mL O2/dL - negligible (~1.5% of total)

• Each Hb molecule carries 4 O2 (one per heme group)
• Hüfner's constant: 1 g Hb carries 1.34 mL O2 when fully saturated
• Normal Hb = 15 g/dL → capacity = 15 × 1.34 = ~20 mL O2/dL blood

CaO2 = (Hb × 1.34 × SaO2) + (0.003 × PaO2)

DO2 = Cardiac Output (CO) × CaO2

• Normal: ~1000 mL O2/min

• Normal at rest: ~250 mL O2/min
• Oxygen extraction ratio = VO2/DO2 = 25% (reserve for increased demand)

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D. Oxygen Therapy

• Patients with chronic hypercapnia have blunted central chemoreceptor response to CO2
• They rely on hypoxic drive (peripheral chemoreceptors, PaO2 <60 mmHg) to breathe
• High-flow O2 → abolishes hypoxic drive → hypoventilation → CO2 retention → CO2 narcosis → respiratory failure
• Target SpO2 = 88-92% in COPD (not 94-98%)
• Venturi mask preferred in COPD (delivers precise, controlled FiO2)

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12. MEGALOBLASTIC ANEMIA - Clinical Case

• Pernicious anemia (most common): autoimmune → anti-parietal cell antibodies + anti-Intrinsic Factor antibodies → loss of IF → B12 malabsorption (terminal ileum)
• Strict vegetarian/vegan (B12 only in animal products)
• Gastrectomy, terminal ileal resection
• Diphyllobothrium latum (fish tapeworm)

• Poor diet (leafy vegetables, liver), alcohol
• Increased demand: pregnancy, hemolytic anemia
• Malabsorption (jejunum), drugs: methotrexate (DHFR inhibitor), trimethoprim, phenytoin

• B12 needed for: (1) methylmalonyl-CoA → succinyl-CoA; (2) regeneration of methionine (B12 + homocysteine + methyl-THF → methionine + THF)
• Without B12: folate trapped as methyl-THF → effectively folate-deficient even if folate intake adequate
• THF derivatives needed for thymidylate synthesis (dTMP for DNA synthesis)
• Result: impaired DNA synthesis, megaloblastic changes in all rapidly dividing cells (RBCs, WBCs, GI epithelium)

• Macrocytic anemia: MCV >100 fL
• Hypersegmented neutrophils (>5 lobes or any cell ≥6 lobes) - hallmark
• Elevated homocysteine (both B12 and folate deficiency)
• Elevated methylmalonic acid (MMA) - only in B12 deficiency (differentiates from folate)
• Low serum B12 or folate; anti-IF antibodies (pernicious anemia)

• Posterior columns: loss of vibration sense, proprioception → sensory ataxia
• Lateral columns (corticospinal tract): UMN signs - spasticity, hyperreflexia, positive Babinski
• Peripheral neuropathy: glove-and-stocking sensory loss, paresthesia
• Dementia, optic neuropathy (severe cases)

• B12 deficiency: IM hydroxocobalamin (1000 µg) × 6 loading doses, then monthly maintenance; oral B12 for dietary cause
• Folate deficiency: oral folic acid 5 mg/day
• NEVER give folate alone if B12 deficiency suspected - corrects anemia but allows neurological deterioration to progress (and may precipitate/worsen SCD)

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13. ACUTE MYOCARDIAL INFARCTION (MI) - Clinical Case

1. Atherosclerotic plaque (lipid core + fibrous cap) in coronary artery
2. Plaque rupture/erosion → exposes subendothelial collagen + tissue factor
3. Platelet adhesion (GPIb-vWF) → activation → TXA2/ADP release → platelet aggregation (GPIIb/IIIa-fibrinogen)
4. Coagulation cascade → fibrin thrombus → total coronary occlusion
5. Ischemia (reversible) → if >20-30 min → necrosis (irreversible)

• Zone of necrosis: Q waves
• Zone of injury: ST elevation
• Zone of ischemia: T wave inversion

• Early: Arrhythmias (VF = most common cause of early death), LV failure
• Late: Cardiogenic shock, papillary muscle rupture (MR), ventricular septal rupture, LV aneurysm, Dressler syndrome (autoimmune pericarditis 2-10 weeks post-MI)

• MONA: Morphine (pain relief), O2 (if SpO2 <90%), Nitrates (vasodilation), Aspirin 325 mg (antiplatelet)
• Dual antiplatelet: Aspirin + Ticagrelor/Clopidogrel
• Anticoagulation: Heparin/LMWH
• Reperfusion: Primary PCI (preferred, within 90 min) or thrombolysis (streptokinase/alteplase) if PCI unavailable within 120 min
• Long-term: Beta-blocker, ACE inhibitor, statin, dual antiplatelet

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14. ACHALASIA CARDIA - Clinical Case

1. Failure of LES to relax on swallowing
2. Absent peristalsis in the body of esophagus

• Loss of inhibitory neurons (VIP/nitric oxide releasing - NANC neurons) in myenteric plexus (Auerbach's plexus) of esophagus → LES cannot relax
• Excitatory cholinergic neurons remain intact → net sustained LES contraction
• Cause: Autoimmune, HSV-1, or Chagas disease (Trypanosoma cruzi destroys myenteric plexus - in South America)

• LES resting pressure = 15-30 mmHg (prevents GER)
• On swallowing: NANC neurons release NO → LES relaxes → food passes
• In achalasia: LES pressure >45 mmHg, does not relax → food accumulates above

• Achalasia: both solids AND liquids from the beginning (neuromuscular problem)
• Carcinoma/stricture: solids first, then liquids (mechanical obstruction - progressive)

• Barium swallow: Dilated esophagus + "bird-beak"/"rat-tail" narrowing at LES
• Esophageal manometry (gold standard): Absent peristalsis + incomplete/absent LES relaxation + elevated LES pressure
• Endoscopy: Rules out malignancy (pseudoachalasia)

• Pneumatic balloon dilation (first-line endoscopic)
• Laparoscopic Heller myotomy (cuts LES muscle) + fundoplication (prevents GERD post-myotomy)
• Botulinum toxin injection into LES (temporary; for poor surgical candidates)
• POEM (Per-oral endoscopic myotomy): newer endoscopic technique
• Medical: Calcium channel blockers/nitrates (partial, temporary benefit)

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15. ROLE OF SURFACTANT AND PATHOPHYSIOLOGY (RDS)

• Composition: ~80% phospholipids (mainly DPPC - dipalmitoylphosphatidylcholine), 10% other lipids, 10% proteins (SP-A, SP-B, SP-C, SP-D)
• Production begins ~24-28 weeks gestation; matures by ~35 weeks

P = 2T/r (P = pressure to keep alveolus open, T = surface tension, r = radius)

• Without surfactant: small alveoli (small r) need enormous pressure → collapse (atelectasis)
• Large alveoli expand and small ones collapse into them

1. Reduces surface tension at alveolar air-liquid interface → ↓ work of breathing
2. Stabilizes alveoli of different sizes:
   • As alveolus shrinks (expiration) → surfactant molecules crowd together → surface tension decreases → prevents complete collapse
   • As alveolus enlarges (inspiration) → molecules spread → surface tension increases → prevents overdistension
3. Prevents pulmonary edema: Low surface tension prevents fluid being drawn from capillaries into alveolar spaces
4. Increases lung compliance: Easier to expand → reduces breathing effort

• Premature infant (<35 weeks) lacks surfactant → high surface tension → alveolar collapse at end-expiration
• Each breath requires massive effort (enormously increased work of breathing)
• Cycle: Hypoxia → acidosis → Type II pneumocyte injury → further surfactant loss → worsening collapse
• Plasma proteins leak into alveoli → form hyaline membranes (hence "hyaline membrane disease")
• V/Q mismatch → progressive hypoxia + hypercapnia

• Premature infant
• Onset within 4-6 hours of birth
• Grunting, nasal flaring, subcostal/intercostal retractions, tachypnea, cyanosis
• CXR: ground-glass appearance + air bronchograms + low lung volumes

• L:S > 2: lungs mature, RDS unlikely
• L:S < 1.5: immature lungs, high risk of RDS

• Antenatal corticosteroids (betamethasone/dexamethasone) to mother: induces surfactant synthesis in fetus - give if delivery <34 weeks
• Exogenous surfactant (poractant alfa, beractant) via ET tube at birth
• CPAP: Keeps alveoli open at end-expiration (maintains PEEP)
• Mechanical ventilation for severe cases

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16. ECG + SIGNIFICANCE OF PR INTERVAL + ARRHYTHMIAS

ECG Waveform Diagram

         R
        /\
       /  \
  P   /    \              T
 /\  /      \            /\
/  \/        \__________/  \___
      Q  S
  |←PR→|←QRS→|←--ST--→|←T→|
  |←———————— QT ———————————→|

ECG Components:

Significance of PR Interval

• Wolff-Parkinson-White (WPW): Accessory pathway (Bundle of Kent) bypasses AV node → short PR + delta wave (slurred upstroke of QRS) → risk of re-entrant tachycardia

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Notes on Arrhythmias

• Sinus tachycardia: HR >100; normal P morphology; causes: fever, anemia, hypovolemia, anxiety, thyrotoxicosis
• Sinus bradycardia: HR <60; normal morphology; causes: athletes, hypothyroidism, vasovagal, beta-blockers, inferior MI
• Atrial Fibrillation (AF):
  • Irregularly irregular rhythm; absent P waves; fibrillatory baseline; narrow QRS
  • Most common sustained arrhythmia
  • Causes: hypertension, valvular disease, IHD, thyrotoxicosis, alcohol
  • Risk: left atrial appendage (LAA) thrombus → stroke
  • Treatment: Rate control (beta-blockers, digoxin, diltiazem) + anticoagulation (NOAC/warfarin) ± rhythm control (DC cardioversion, amiodarone)
• Atrial Flutter: Sawtooth flutter waves at 250-350/min; regular 2:1 or 4:1 block → ventricular rate 75-175/min
• SVT (AVNRT - most common type):
  • Sudden onset, narrow QRS, regular, HR 150-250/min; P waves hidden or retrograde
  • Treatment: Valsalva maneuver → adenosine IV (blocks AV node transiently) → AV nodal blockers → DC cardioversion

• Ventricular Tachycardia (VT):
  • Rate >100/min, wide QRS, AV dissociation, fusion/capture beats
  • Causes: IHD (most common), cardiomyopathy, electrolyte imbalance
  • Pulseless VT: defibrillation; hemodynamically stable VT: amiodarone, lidocaine, or DC cardioversion
• Ventricular Fibrillation (VF):
  • Chaotic, irregular, no organized QRS; immediately fatal without treatment
  • Most common cause of sudden cardiac death post-MI
  • Treatment: Immediate unsynchronized DC defibrillation + CPR
• Torsades de Pointes:
  • Polymorphic VT; QRS "twists" around isoelectric baseline; rate 200-250/min
  • Associated with prolonged QT interval (drugs: amiodarone, sotalol, quinidine, haloperidol, erythromycin; electrolytes: hypokalemia, hypomagnesemia)
  • Treatment: IV magnesium sulfate; remove causative drug; correct electrolytes; temporary pacing (overdrive pacing)

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17. IONIC BASIS OF RESTING MEMBRANE POTENTIAL (RMP)

• Nerve/skeletal muscle: ~-70 mV
• Cardiac ventricular muscle: ~-90 mV
• Smooth muscle: ~-55 to -65 mV

• At rest, membrane is predominantly permeable to K+ via K+ leak channels (inward rectifier K+ channels)
• K+ diffuses OUT down its concentration gradient → inside becomes negative (leaves behind negative charges)
• This creates an electrical gradient opposing further K+ exit
• K+ equilibrium potential = -94 mV (close to actual RMP)

• Membrane has some resting Na+ permeability (small Na+ leak)
• Na+ leaks IN → partially depolarizes cell
• Actual RMP (~-70 mV) is less negative than K+ equilibrium (-94 mV) due to this Na+ leak

• Takes permeability and concentration of all ions (K+, Na+, Cl-) into account
• At rest: PK >> PCl >> PNa (K+ permeability dominates)
• GHK predicts RMP of -70 mV accurately

• Pumps 3 Na+ out and 2 K+ in per cycle (electrogenic - net 1 positive charge out → hyperpolarizes by ~3-5 mV directly)
• More importantly: maintains K+ and Na+ concentration gradients upon which diffusion potentials depend
• Without Na+-K+ ATPase: gradients would dissipate → RMP lost

• Large negatively charged proteins inside cell cannot diffuse out
• They attract cations (K+) and repel anions from inside → contribute to intracellular negativity

RMP is mainly due to K+ diffusion outward. Na+-K+ ATPase maintains the gradients. Na+ leak partially depolarizes. Intracellular proteins add to negativity.

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18. TUBULOGLOMERULAR FEEDBACK (TGF)

• Macula densa: Specialized epithelial cells at the junction of thick ascending limb and early distal tubule - lies adjacent to its own glomerulus
• Juxtaglomerular (JG) cells: Modified smooth muscle cells in the afferent arteriole wall - secrete renin
• Extraglomerular mesangial cells: Between macula densa and JG cells

1. ↑ GFR → ↑ tubular flow → ↑ NaCl concentration/delivery at macula densa
2. Macula densa senses ↑ NaCl via Na+-K+-2Cl- cotransporter (NKCC2)
3. Macula densa releases adenosine (and ATP)
4. Adenosine acts on A1 receptors on afferent arteriole → vasoconstriction
5. ↑ Afferent resistance → ↓ glomerular capillary pressure → GFR falls back to normal
6. Renin release from JG cells is also suppressed

1. ↓ NaCl at macula densa → less adenosine → afferent arteriole dilates
2. Macula densa also signals JG cells → ↑ renin release → angiotensin II → efferent arteriole constriction → maintains GFR

• Prevents large swings in GFR within a single nephron
• Protects distal tubule from being overwhelmed by fluid
• Coordinates filtration with reabsorptive capacity
• Part of renal autoregulation (maintains GFR relatively constant when BP is between 80-180 mmHg)

• Diabetes (early): Hyperfiltration partly due to impaired TGF (glucose + Na+ reabsorbed by SGLT2 in PCT → less NaCl reaches macula densa → afferent dilation → ↑ GFR)
• SGLT2 inhibitors (dapagliflozin): restore TGF by blocking PCT Na+-glucose reabsorption → more NaCl to macula densa → TGF activation → ↓ GFR → renoprotective effect
• NSAIDs: Block prostaglandins that dilate afferent arteriole → may reduce GFR especially in low-flow states
• Theophylline (adenosine antagonist): Blunts TGF

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19. REGULATION OF BODY TEMPERATURE

• Circadian variation: lowest at 4-6 AM, highest at 6-10 PM
• Higher in females (especially post-ovulation due to progesterone)

• BMR: liver, brain, heart produce most heat at rest
• Skeletal muscle activity (exercise → 10-15× increase)
• Shivering thermogenesis: involuntary skeletal muscle contractions
• Non-shivering thermogenesis: Brown adipose tissue (BAT) - UCP-1 (thermogenin) uncouples oxidative phosphorylation → heat (important in neonates)
• Hormones: T3/T4, epinephrine → ↑ BMR → ↑ heat

1. Radiation (~60% at rest): emission of electromagnetic waves; most important at thermoneutral temperatures
2. Conduction: Direct contact with cooler objects
3. Convection: Moving air/water carries heat away
4. Evaporation (most important when Ta > Tb): sweating - ~0.58 kcal per gram of sweat evaporated
5. Insensible perspiration: ~600 mL/day continuous, not perceived

• Peripheral: Cold receptors (Aδ fibers) and warm receptors (C fibers) in skin → rapid response to environmental temperature changes
• Central: In hypothalamus (most sensitive), spinal cord, abdominal viscera → monitor core temperature

• Exogenous pyrogens (bacteria, viruses, toxins, antigen-antibody complexes)
• Activate macrophages → release endogenous pyrogens: IL-1, IL-6, TNF-α
• Act on hypothalamus → ↑ COX-2 → ↑ PGE2 → raises the hypothalamic set-point
• Body responds as if "too cold": vasoconstriction (feeling cold/chills), shivering → temperature rises to new set-point
• Antipyretics (aspirin, paracetamol): inhibit COX → ↓ PGE2 → set-point resets to normal → sweating + vasodilation → temperature falls

• Failure of thermoregulation at very high ambient temperature/exertion
• Core temperature >40°C, anhidrosis (failure of sweating), CNS dysfunction (confusion, seizures, coma)
• Medical emergency: rapid external cooling (ice water immersion)

• Core temperature <35°C
• Mild (35-32°C): shivering, tachycardia, impaired judgment
• Moderate (32-28°C): confusion, no shivering, bradycardia
• Severe (<28°C): cardiac arrhythmias, coma, death
• Paradoxical undressing; cold diuresis (renal tubule insensitivity to ADH)

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MASTER QUICK-REFERENCE INDEX

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Sources: Guyton & Hall Textbook of Medical Physiology, Costanzo Physiology 7th Ed, Robbins & Kumar Basic Pathology, Cellular & Molecular Immunology (Abbas), Greenfield's Surgery. All content verified against authoritative medical textbooks.