KICK THE BOARDS USMLE STEP 1 Physiology Prepared by Dr. Irfan Mir
KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
CELL PHISIOLOGY * Cell mem composed of phospholipids bilayer which contain glycerol back bone. * Glycerol back bone composed of head (hydrophilic) and two fatty acid tails (hydrophobic). Tails face each other. * Lipid soluble substance cross cell mem whereas water soluble pass through channel, pores and carriers. * Integral protein span the entire mem (eg. Ion channel) whereas, peripheral protein located either inter or extra cellular side. * Tight Junction (zona occludes) ------- are attachment b/w cells serve intracellular pathway for solute. It may be tight (Impermeable) as in renal distal tubules or leaky (permeable) as in renal proximal tubule or gall bladder. * Gap junction -- is attachment b/w cells which permit IC communication eg. In myocardial cells. * Simple diffusion -- is the transport which is not carrier mediated. It occur down an electrochemical gradient does not require energy passive. Diffusion can be measured by J = - PA (C1 - C2) (J= flow, P= permeability, A= area, C= concentration) * Carrier mediated transport shows stereospecificity, saturation and competition. Stereospecificty means D-glucose (natural isomer) can transported where as L-glucose (L-isomer) can not. Saturation means transport as the concentration until carriers are saturated called Tm (transport maximum) Competition means structurally related solute compete for transport site. eg. (Galactose is competitive inhibitor of glucose in small Intestine). * Facilitated diffusion -- occur down an electrochemical gradient, does not require energy is passive. It is carrier Mediated and more rapid than simple diffusion. * Primary Active transport -- occur against the electrochemical gradient (up hill). It utilize metabolic energy (from terminal bond of ATP) is active. It is also carrier mediated ( exhibit stereospecificity, saturation and competition) . Eg. Na+ - K+ ATPase (usual stoichiometry is 3Na / 2K) ,Ca++ ATPase in sarcoplasmic reticulum, K+ - H+ ATPase in parietal cells. * Secondary Active transport -- in which transport of two or more solute is coupled. One of the solute is transported down hill (usually Na+) which provide energy for uphill transport of other solute. Metabolic energy provided indirectly from Na gradient. Thus the inhibition of Na+ - K+ ATPase results into inhibition of Secondary transport. Eg. Na+ - glucose Cotransport in renal proximal tubule, Ca++ - Na+ exchange, Na+ - H+ exchange. Poisoning the Na+ - K+ pump eventually results into inhibition of Ca++ - Na+ exchange due Na+ imbalance across cell mem. * Cotransport or symport is transport of solute in the same direction whereas, Counter transport or antiport or exchange is the transport of two solute in opposite direction to each other. * Osmolarity is the conc (C) of osmotically active particle in a solution. Osmolarity = g C (g is no of particle in the solu. * Solution with high osmolarity is hyperosmotic, low osmolarity is hypoosmotic, and same osmolarity is isosmotic. * Osmotic Pressure (van’t Hoff’s Law) depends on the conc of osmotic particles. in solute particle results in osmotic P. It can be measured by = g RT C (Where R is gas constant 0.082L - atom/mol - K. and T is absolute temp K). * Reflection coefficient is the no b/w zero & one. It explains the ease with which solutes permeate the mem. If Reflection coefficient is 1 the solute is impermeable & when it is zero solute is permeable. eg. Reflection coefficient of albumin (big solute) is 1 where as urea (small solute) is zero. * Ion channels are open or closed by gates. It may be voltage gated channel which open or closed by change in mem potential. Eg Na channel in nerve action potential. It may be Ligand (chemical) gated channel which open or closed by hormones, second messenger, neurotransmitters. * Diffusion potential is the potential difference generated across a mem because of conc difference of an ion. * Equilibrium potential is the diffusion potential which exactly balance (opposes) the tendency for diffusion caused by conc difference. There is no more net movement because electrical driving forces on ion are equal and opposite.. * Nernst equation is used to calculate equilibrium potentials. E = -2.3 RT log10 [Ci] zF [Ce] E Na+ is + 65mV E Ca++ is + 120Mv E K+ is - 85mV E Cl- is - 90mV * Resting mem Potential is the measured potential difference in mV (millivolts), it is established by diffusion potential. The resting mem potential of nerve is -70 mV. At rest nerve mem is far more permeable to K+ than to Na+ at rest. * Threshold is the mem potential at which occurrence of action potential is inevitable. Inward current depolarize the mem to Threshold.
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
* Upstroke of action potential is depolarization cause rapid opening of the activation gates of Na+ channel. Na enters into the cell. * Depolarization also open K+ gates and closes the Na+ channel gates but at slower rate. This combined effect make K+ conductance higher than Na+ conductance in last quarter of depolarization which make mem potential to Repolarize. * Repolarization is caused by outward K+ current. * Over shoot is the portion of action potential when mem potential is positive whereas Under shoot (hyperpolarization) makes the mem potential more negative (close to K+ equilibrium potential). * Absolutely Refractory period is the period during which another action potential cannot be elicited no matter how large the stimulus is. * Relative refractory period begins at the end of absolute refractory period and continuous till mem potential return to its resting potential. Stronger than usual current can elicit the action potential. * Fiber size and myelination can the conduction velocity of action potential. Remember myelinated nerve exhibit saltatory conduction because action potential can be generated only at the Node of Ranvier. * End Plate potential (EPP) in the postsynaptic mem is not an action potential but a depolarization of specialized muscle end plate. Once the end plate region is depolarized local current cause depolarization and action potential in the adjacent muscle. * Excitatory postsynaptical potential (EPSP) bring the cell closer to fire action potential where as Inhibitory Postsynaptical potential (IPSP) hyperpolarize the postsynaptical cell by opening Cl- channels.. * Thick filament contain myosin present at A band. vs. Thin filament contain actin, tropomyosin & troponin present at band. * Myosin head bind ATP and actin and are involved in cross bridging formation. * T tubule are present at the junction of A band and band. It carry depolarization to the interior of the cell. * Skeletal muscle contraction -- sarcoplasmic reticulum (SR) are internal tubular structure site of Ca++ storage and release. Ca bound loosely to calsequestrin with in SR & it release upon depolarization bring by T tubules. Released Ca+ bind to troponin C on the thin filament causing conformational change in Troponin (which is tropomyosin moving out of way so that cross bridge cycle can begin). Actin myosin binds and filament slide over each other and ATP is hydrolysed. * Length Tension relationship :1. Passive tension -- is tension developed by stretching to Fixed length (preload). 2. Total Tension -- is tension developed when the muscle is stimulated to contract at different length. 3. Active Tension -- is the difference b/w total tension and passive tension. * Smooth muscle contraction -- smooth muscle has thick & thin filament & are not arranged in sarcomere. (vs. striated m) There is no troponin instead Ca++ regulate myosin on thick filament Ca++ enter in the cell across cell mem it may cause release of additional Ca++ from SR via Ca++ - gated channels. Hormones and neurotransmitters also release Ca++ from SR through IP3 gated Ca++ channels. IC Ca++ . Ca++ bind to Calmodulin and Ca++ - calmodulin complex bind to and activate myosin light chain kinase which further phosphorylate myosin and allow it bind with actin. Contraction follow. * Dephosphorylation of myosin cause relaxation where as in striated muscle Ca++ uptake cause relaxation. Remember in heart and striated muscle Ca binds with troponin and in smooth muscle Ca binds with calmodulin. Figs:
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
ENODCRONOLOGY ** SECOND MESSENGER SYSTEM :--------------------------------------------------------------------------------------------------------------------------------------CYCLIC AMP
IP3 Ca++
STEROIDS
TYROSINE KINASE
CYCLIC GMP
--------------------------------------------------------------------------------------------------------------------------------------CRH ACTH TSH PTH ADH ( V2 ) 1, 2, 2 FSH, LH HCG M2 MSH Calcitonin Glucagon Secretin Dopamine
GnRH TRH GHRH ADH ( V1 ) Oxitocin 1 Angiotensin II CCK M1 , M3 GABA
Mineralcorticoids Glucocorticoids Estrogen Progesterone Testosterone Vit D T3, T4
Insulin IGF
ANF EDRF (NO)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------* TSH, FSH, LH, HCG are the member of same glycoprotein bears subunit (identical) & subunit (unique for hormone). * ACTH, MSH, Lipotrophin, Endorphin, all derived from POMC. * MSH, and MSH Rudimentary in adult. * GHRH GH (acidophillic stain). Functions :- * Glucose uptake ( Diabetogenic ) * lipolysis * Protein Synthesis ( LBM ) * Production of IGF (insulin like growth factor) * Somatostatins and Somatomedins have imp negative feed back function. * Somatostatin block GHRH effect on AP. vs. Somatomedins cause +ve feedback on the release somatostatin from HT -------------------------------------------------------------------------------------------* PL (acidophilic to chromophobic stain). PL secretion by TRH and inhibit by Dopamine. Function:-* Lactogenesis * Breast development * Inhibit Ovulation ( via Syn of GnRH ) * inhibit spermatogenesis (via GnRH) Pathology :- * Failure to lactate * Failure to ovulate * Galactorrhea (hypothyroidism can cause increase in TRH with resultant galactorrhea) -------------------------------------------------------------------------------------------* ADH originate in supraoptic nuclei of hypothalamus ( Post lobe ). Act on receptors V1 ( vasoconstriction ) and V2 ( distal tubule and collecting duct permeability) * Oxitocin originate in paraventricular nuclei of hypothalamus ( post lobe ). Major stimulus for secretion is Suckling, sight and sound of infant. * Neurophysin is CNS carrier protein for both hormone (ADH, Oxitocin). --------------------------------------------------------------------------------------------------------------------------------------------------------------------------* Causes of or secretion of ADH :: Secretion of ADH vs. secretion of ADH ----------------------------------------------------------------------------------------------------------------------------------------------------------------------* serum osmolarity * serum osmolarity * Vol contraction * Ethanol * Pain, Nausea (strong) * Agonist * Hypoglycemia * ANP * Necotinic opiate * Antineoplastic drug -----------------------------------------------------------------------------------------------------------------------------------------------------------------------
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
* Function of Oxitocin : Myoepithelial contraction of mammary gland, Milk ejection, Contraction of uterus, Dilatation of Cervix and Orgasm. ( it can be used to induce labour ). * TRH TSH T3, T4 ( stored in lumen). (Basophilic and chromophobic stain) * Iodide pump ( I - ) present in thyroid follicular epithelial cell. * Iodide pump Inhibit by Thiocyanate and Perchlorate ion. * T3, T4 syn can be inhibited by dosis of Iodine ( I 2 ) this is called Wolf Charkoff Effect. * T3 is 4 times more potent than T4. * Three stages of TH syn :- 1. Oxidation :- 2 I - ( Iodide ) I2 ( iodine ) --------- ( Propylthiouracil inhibit oxidation). 2. Organification :- I 2 + Tyrosine of Thymoglobulin MIT + DIT 3. Coupling reaction :- MIT + DIT Triidothyroxine T3 ( active form ) DIT + DIT Thyroxine T4 * Befor release Iodinated thyroglobulin first must be taken back into the follicular cell from lumen for digestion of thymoglobulin by lysosomal enz to release T3 T4. ( left over MIT and DIT are digested by thyroid deiodinase ). * T3 T4 circulate by Thyroid Binding Globulin. * Conversion of T4 into T3 (active form) and Reverse T3 (inactive form) take place in target tissue by enz Iodinase. * Enz 1,5 monodeiodinase cause break down of T3 and Reverse T3, its deficiency results into T3 and Reverse T3. * Function of thyroid hormone :1. Growth, Bone formation, and maturation. 2. CNS -- Prenatal CNS maturation In Adults ---- Hyperthyroidism ( Grave’s dis, Plummers $ ) Hyperexcitability, Irritation. Palpitation etc. Hypothyroidism ( Myxedema, Cretinism, Hashimoto thyroiditis, De Quervian thyroiditis, Reidal thyroiditis ) mental capacity, impaired memory, slow speech, listlessness, Somnolence, etc. 3. Autonomic nervous sys :- Adrenergic Stimulation. 4. BMR :- O2 consumption and BMR except in Spleen, Gonad and Brain (results into body temp). Syn of Na+ K+ ATPase (results into O2 consumption) HR, Ventilation (ensure more O2 delivery to tissue) 5. Metabolic effect are over all catabolic . * Grave dis in which IgG ( thyroid stimulating imunoglobin) T3, T4 --------------------------------------------------------------------------------------------------------------------------
* PTH is secreted by Chief cells and regulate serum Ca++. * 1,25 Dihydrocholecalciferol is active form of Vitamin D, produce by 1 hydoxylase in kidney to Provide Ca++ & Phosphate for normal bone mineralization. * Calcitonin Syn and secreted by Parafollicular cell ( C.cells ) of thyroid. Its major action is to inhibit bone Resorption. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------PTH VIT D CALCITONIN ------------------------------------------------------------------------------------------------------------------------------------------------------------------------Stimulus for secretion: Serum Ca++ Serum Ca++ * Serum Ca++ Mild in serum Mg Serum Phosphat Severe serum Mg inhibit secretion. PTH Action on Bone :-
Resorption
Resorption
* Reabsorption
Action on Kidney :-
Ca++ Reabsorption Ph Reabsorption
Ca++ Reabsorption Ph Reabsorption
Action on Intestine :-
Ca++ Absorption (via Vit D)
Ca++ Absorption (via vit D Ca++ binding Protein)
Overall effect :-
Serum Ca++ Serum Ca++ * Serum Ca++ Serum Ph Serum Ph ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Resorption of organic matrix of the bone is reflects in Hydroxyproline Excretion. * PTH Ca++ reabsorption at distal tubule where as in proximal tubule PTH inhibit Ph reabsorption with resultant excretion of nephrogenous cyclic AMP. * PTH Vit D production ( indirectly ) by stimulating 1 Hydroxylase. * Vit D mineralize new bone by Ca++ and Ph in serum. * Hypoparathyroidism Tetany ( Ca++, Ph ).
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
* Hyperparathyroidism Ca++, serum Ph, phosphaturia, Urinary cAMP, Bone resorption ( with resultant in calcitonin & Vit D). * Pseudohypoparathyroidism ( Albright hereditary Osteodystrophy ) is due to defective G Protein in target tissue with resultant resistance to PTH which cause PTH, Ca++, Ph. * Vit D Deficiency Osteomalacia and Rickets . Diet cholecalceferol 7 Dehydrocholecalciferol ( In skin through ultra voilet light ) 25.OH. Cholecalciferol ( In Liver ) Kidney ( 1 Hydroxylase ) ( PTH, Ca++, Ph ) 1,25 hydrocholecalciferol 24,25 (OH)2 Cholecalciferol
* Remember PTH, Ca++, and Ph have positive stimulating effect on enzyme 1 Hydroxylase hence ↑ it activity. ------------------------------------------------------------------------------------------------------* Zona G -- Mineralcorticoids (Aldosterone) Zona F -- Glucocorticoids (Corticosteroids) Zona R -- Androgen (Testosterone, Estradiol) **
Cholesterol Pregnenolone
17 Hydroxylase
17 Hydroxypregnenolone
17 . 20 Lyase
Dehydroxyandrosterone
3 hydroxysteroid Dehydrogenase Progesterone 21 hydroxylase 11 Deoxycorticosterone 11 Hydroxylase corticosterone
3 hydroxysteroid dehydrogenase 3 hydroxysteroid dehydrogenase Hydroxyprogesterone Androstenidione 17, 20 lyase 17 Osteroid dehydrogenase 21 hydroxylase and Aomatase 11 Deoxycortisol Testosterone / Estradiol 11 Hydroxylase Cortisol
AT II & ↑K+ Aldosterone synthase Aldosterone .
* Glucocorticoids :- CRH (from paraventricular nuclei) ACTH (AP) . (Both synthesize by POMC). Release in circardian rhythm, Cortisol at 6 AM and at 12 midnight. * ACTH up regulate its own receptor. Cortisol cause -ve feed back inhibition to both CRH and ACTH. * Glucocorticoids are essential in response to stress. cortisol level cause bone resorption. * Glucocorticoid Functions :- 1. Gluconeogenesis :- protein catabolism and protein syn. lipolysis glucose utilization (hyperglycemic) 2. Anti inflammatory :- syn of lipocortin inhibit phospholipase A2 inhibit IL2 ( so inhibit T.cell proliferation ) inhibit histamine and serotonin. 3. Maintain vascular responsiveness to catecholamine. * Mineralcorticoids :* Hypovolemia Renin AT I AT II Aldosterone Na+ reabsorption, K+ secretion, H+ secretion. * Hyperkalemia cause Aldosterone secretion. * Androgens :- Androstenidione produce Testosterone in testes and Estraidol in ovary. Deficiency of 17, 20 lyase Absence of Androgen. Deficiency of 3 hydroxysteroid dehydrogenase Absence of every thing. Deficiency of 21 hydroxylase Absence of Glucocorticoids and Mineralcorticoids. Def of 11 hydroxylase Absence of Cortisol only ( because 11- deoxycorticosterone has partial Aldosterone activity 3% )
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
* Pathology :- 1. Adrenocortical Insufficiency (Adison dis) . Primary Commonly cause by autoimmune destruction of Adrenal cortex. glucocorticoids, mineralcorticoids and androgen POMC, ACTH. Hypoglycemia, hyperpigmentation, vol contraction, hyperkalemia, metabolic acidosis Aldosterone def. Secondary Caused by ACTH . Does not exhibit vol contraction, hyperkalemia, metabolic acidosis because aldosterone is normal. 2. Adrenocortical Excess . cortical & androgen level, hyperglycemia, muscle wasting, central obesity, moon face buffalo hump, supraclavicular fat, poor wound healing, striae, hypertension, osteoprosis, virilization of female.
Cushing $ commonly cause by Glucocorticoid therapy and adrenal gland hyperplasia. Cushing Dis Overproduction of ACTH. 3. Hyperaldosteronism (Conn $) -- cause by tumor.( hypertension, hypokalemia, metabolic alkalosis, renin secretion ) 4. Water house Friderichson $ :- Catastrophic adrenal insufficiency due to hemorrhagic necrosis of adrenal cortex often because of Meningococcal meningitis . 5. Adrenogenital $ :- 21 hydroxylase deficiency -- Cortisol and Aldosterone. Hydroxyprogesterone and progesterone. ACTH hyperplasia of Zona F and Zona R . Adrenal androgen. Virilization of female (early linear growth, pubic and axillary hair). suppress gonads function in both sexes. -------------------------------------------------------------------------------* Endocrine Pancrease :- cells ---- Outer cell islet ---- Glucagon cells ---- Central islet ---- Insulin cells ---- Intermix ---- Somatostatin, Gastrin. Pancreatic polypeptide :------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Insulin ( Tyrosinekinase receptor) stimulation for secretion Over all Effect -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- blood glucose blood glucose AA Fatty acid Glucagon GIP --------------------------------------------- AA GH --------------------------------------------- Fatty acid hypokalemic Cortisol --------------------------------------- Ketoacid ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Glucagons ( cAMP mech ) Stimulation for secretion Over all Effect --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Blood glucose Blood glucose AA CCK --------------------------------------------- Fatty acid EN, Nor EN, Ach ------------------------------- Ketoacid ( Hydroxubutyrate and acetoacetate ) ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Glucagon act only on liver Glycogen break down. Glucagon Fructose 2,6 Biphosphate production and Phosphofructokinase activity. ( That's why also cause gluconeogenesis, in addition to Glycogenolysis, Lipolysis, and Ketone production).
* Insulin consist of subunit and subunit among which subunit have tyrosine kinase activity. * Insulin down regulates its own receptor. Receptor in starvation and in obesity. Action :- uptake of glucose and promote glycogen formation. Inhibit Glycogenolysis and Gluconeogenesis. Decreases Fatty acid , ketones, AA, and serum K+ concentration Inhibit lipolysis and stimulate fat deposition. * Insulin def → into hypokalemia, hypotension and nocturia. Also ketosis which results into metabolic acidosis compensatory hyperventilation.
* Somatostatin :- Inhibit secretion of Glucagon, Insulin, Gastrin, and Intestinal absorption of Glucose. * insulin secretion is mediated by ca++ channel opening in cell. Blood glucose, somatostatin and EN, Nor EN insulin secretion.
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KICK THE BOARDS “USMLE STEP 1”
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* Testosterone synthesize by 5 reductase and secreted by Leydig cells. Cholesterol desmolase
Cholesterol Pregnenolone LH 17 hydroxypregnenolone Dehydroxyandrosterone Androstenidione 17 OH steroid Dehydrogenase Testosterone 5 reductase Dihydrotestosterone (active form)
( Inhibin release from sertoli cells, it cause - ve feed back affect on the release of FSH from Ant pituitary ) * GnRH originate from arcuate nuclei of hypothalamus & secrete in pulsatile manner. GnRH upregulate its own receptor in AP. Testosterone Action :- * Prenatal differentiation of wolfian duct and external genitalia. * Develop male Secondary sexual characteristics at puberty. * Cause pubertal growth spurt. * Maintain spermatogenesis (by paracrine effect of testosterone) and increases libido. * Size and secretory activity of epididymus, Vasdefrens, prostate and seminal vesicle. * 5 reductase inhibit by Finastride it can be used in BPH. ----------------------------------------------------------------------------------------* ESTROGEN AND PROGESTERONE :HT GnRH AP
* FSH and LH Cause Steroidogenesis in ovarian follicle & corpus luteum. Follicular development beyond the antral stage. Ovulation Leutinization
LH
FSH
Theca cell Granulosa cell aromatase Testosterone ( Androgen ) Estrogen (convert Androgen into estrogen)
LH FSH Cholesterol Pregnenolone 17 Hydropregnenolone dehydroepiandrosterone androstenidione testosterone (theca cell) ↓ Aromatase 17 estradiol. (granulosa cells)
* Aromatase convert testosterone into 17 Estradiol. * In male FSH cause spermatogenesis in sertoli cell where as in female it cause 17 Estradiol synthesis in granulose cell. * In male LH hormone cause testosterone synthesis in leydig cells where as in female it cause testosterone synthesis in theca cells.
* Estrogen Function :1. - ve and + ve feed back effect on FSH and LH secretion. ( where as progesterone cause - ve feed back ) 2. Maintainance and Maturation of fallopian tube, uterus, cervix, and vagina. 3. Development of female sec sexual characterstics. 4. Development of breast. 5. Upregulate estrogen, LH, and progesterone Receptor. 6. Development and proliferation of granulose cell. 7. Maintain pregnancy. 8. Lower uterine threshold to contractile stimuli during pregnancy vs.(progesterone Raise uterine threshold to contractile stimuli during pregnancy)
9. Stimulate PL secretion but block its action on breast.
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KICK THE BOARDS “USMLE STEP 1”
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* Progesterone Function :1. - ve feed back effect on FSH, LH. ( where as estrogen cause both - ve and + ve feed back ) 2. Maintain secretory activity of uterus in luteal phase. 3. Maintain pregnancy. 4. Raise uterine threshold to contractile stimuli during pregnancy vs. Estrogen Lower uterine threshold to contractile stimuli during pregnancy. 5. Responsible of development of breast. + ve & - ve FEED BACK CONTROL OF MENSTRUAL CYCLE. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------Phase of Cycle Hormone Type of Feed Back Site ------------------------------------------------------------------------------------------------------------------------------------------------------------------------Follicular Phase Estrogen - ve AP Mid Cycle Estrogen + ve AP (ovulation occur) Luteal Phase Estrogen - ve AP Progesterone - ve HT ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Fig:
* Menstrual cycle :1. Follicular phase (day 5 - 14) :- In which Primodial follicular development and uterus proliferate. Estradiol steadily and FSH, LH suppressed And Progesterone is low. 2. Ovulation (day 15) :- Occur 15 days prior to menses regardless of cycle length. Estradiol + ve feed back on FSH, LH (responsible for LH surge). Ovulation occur as a result of estrogen induced LH surge. Estrogen just after ovulation and again in leuteal phase (source of this is corpus leuteum) Cervical mucous and become less viscous. 3. Leuteal Phase (day15 - 28) :- Corpus leuteum develop and syn of estrogen and progesterone occur from it. vascularity and secretory activity of endometrium.. Basal body temp (progesterone act on HT thermoregulatory center) If fertilization not occur corpus leuteum regresses Estradiol and Progesterone. If fertilization occur Estradiol and progesterone keep steadily. 4. Menses (day 1 - 4):- Is sloughing of endometrium because of with drawal of Estradiol and progesterone. ----------------------------------------------------------------------------------------
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KICK THE BOARDS “USMLE STEP 1”
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* PREGNANCY :-
*1ST TRIMESTER :- HCG stimulates corpus leuteum to produce Estradiol and progesterone. HCG peak occur at week 9 and than it declines. *2nd & 3rd TRIMESTER : Progesterone produce by placenta & estrogen produce by fetal adrenal gland & placental Interplay. Major Placental Estrogen is Estriol. HPL (Human Placental Lactogen).has GH and PL like effect produce through out pregnancy * PARTURITION :- Initiating event is unknown. (there is no change of blood oxitocin level prior to labor even though it is potent stimulator of uterine contraction) * LACTATION :- PL steadily during pregnancy but estrogen and progesterone block the action of PL on breast. After parturition estrogen and progesterone and lactation occur. Ovulation is suppressed by PL because PL inhibit GnRH secretion from HT with resultant in FSH and LH. PL also antagonise the action of FSH and LH on ovaries. Suckling stimulates both oxitocin and PL secretion. --------------------------------------------------------------------------------------------GI PHYSIOLOGY * STRUCTURE AND INNERVATION : Epithelial cell may be secretive or absorptive. Muscularis mucosa --- contraction cause change in surface area. Circular muscle --- contraction cause decrease in diameter of the lumen. Longitudinal muscle --- contraction cause shortening of GI segment. Submucosal plexus and Myenteric plexus -- is enteric nervous sys which integrate and coordinate the motility, secretion and Endocrine function of GI tract. Fig:
* INNERVATION OF GI TRACT :- consist of extrinsic nervous sys and intrinsic nervous sys. Extrinsic nervous sys:- Comprise of Sympathetic and Parasympathetic nervous sys. Parasym is Excitatory via vagus & pelvic nerves where as sym is inhibiting originate from T8 - L2. ( Vagus supplies to esophagus , stomach, pancreas & upper large intestine where as pelvic supplies to lower large intestine, rectum and anus )
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Preganglionic cholinergic fiber synapse in prevertebral ganglion. Post ganglion adrenergic fiber synapse in submucosal and myenteric plexus. Some direct post ganglionic adrenergic innervation to blood vessel & smooth muscle also occur here. Intrinsic nervous sys:- Intrinsic sys relay information to and from GI to CNS. Intrinsic sys also relay information with in GI by local reflexes. Myenteric plexus (Auerbach,s plexus) control motility of smooth muscle Submucosal plexus (Meissner,s plexus) receive sensory information from chemo and mechano receptor and control secretion and blood flow. * GI HORMONES :Hormones (only 4) ---------- Gastrin , CCK, Secretin, GIP --- It enter portal and sys circulation and act on distal sites. Paracrine (only 2) ----------- Somatostatin and Histamine --- Release from GI cells and act on short distance. Neurocrine (only 3) ------- VIP(vosotive intestinal peptide), Gastrin releasing peptide (Bombesin), Enkephalin (met E, leu E) Neurocrine synthesize in neuronal body move down by axons & release by nerve action potential. * Gastrin ---- Little gastrin have 17 AA. Big gastrin have 34 AA (it is not a dimer of little gastrin). Gastrin’s 4 C terminal AA contain biologic activity. Gastrin is a potent H+ releaser than histamine. CCK also has gastrin like activity . * Secretin --- all AA require for biologic activity.
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Hormones Homology Site of secretion Stimulus for secretion Action ------------------------------------------------------------------------------------------------------------------------------------------------------------------------Gastrin CCK G Cell (stomach) Small peptide, AA specially gastric H+ secretion. Phenylalanine and Tryptophan stimulate growth of gastric mucosa. are potent stimulater. (prietal cell, mucosa of intestine & colon) Distention of stomach . Vagus via GRP.(atropin does not inhibit Gastrin release because mediator of gastrin release is GRP not Ach) Inhibit by H+ in stomach via Somatostatin. CCK (33AA)
Gastrin
Secretin
Glucagon
I cell of doudenum & Jejunum
S cell doudenum
Small peptide and AA. fatty acid. monoglycerides. (but not triglycerides)
H+ and fatty acid in Doudenum
Contraction of gallbladder & relax sphincter of oddi. Secrete pancreatic enz. Secrete pancreatic HCO3 via secretin. Growth of endocrine pancrease & gall bladder mucosa. Inhibit gastric emptying. Stimulate pancreatic HCO3 and H2O secretion. Stimulate biliary HCO3 secretion. growth of exocrine pancrease. Inhibit H+ secretion. Inhibit gastrin on growth of gastric mucosa.
(Gastric Inhibitory peptide) GIP Secretin Doudenum and Fatty acid, AA, & Orally administered Stimulate insulin release. Glucagon jejunum Glucose. Inhibit H+ secretion. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* GI paracrine: Somatostatin -- Secreted in response to H+ through out GIT, & its secretion is inhibited by vagus nerve. Somatostatin inhibits all GI hormone and gastric H+ secretion Histamine ------- Secrete by mast cell induce gastric H+ secretion Histamine also potentiate its effect on Ach and gastrin H+ secretion. * GI neurocrines: VIP Cause GI smooth muscle relaxation, stimulate pancreatic HCO3 secretion & inhibit Gastric H+ secretion. VIP producing pancreatic tumor of islet cell pancreatic cholera GRP (bombesin) -- release from nerve ending by vagal stimulation stimulate Gastrin release. Enkephlins -- Contract GI smooth muscle of lower esophageal, pyloric, and iliocecal sphincter. Enkephlins also inhibit intestinal secretion of fluid and electrolytes.
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* GI MOTILITY :- Contractile tissue of GIT is unitary smooth muscle except pharynx, upper 1/3 of esophagus and external anal sphincter which are straited muscle. Phasic Contraction ---- contraction and relaxation found periodically in esophagus, antrum and intestine. Tonic contraction ------- found in lower esophagus sphincter, orad stomach, iliocecal and internal anal sphincter. * Slow wave are oscillating mem potential which is essential to smooth muscle. * Slow wave are not action potential but they do determine the pattern of action potential and contraction. * Depolarization of slow wave bring mem potential closer to threshold to initiate action potential. * Frequency of slow wave not influence by neuronal or hormonal input where as action potential yes. * Frequency of slow wave lowest in stomach (3/min) and highest in doudenum (12/min). * SALIVA :- There are 3 major glands, Parotid, maxillary and sublingual gland.(myoepithelial and ductal cells contract to eject saliva in mouth)
* At lowest flow rate saliva has lowest osmolarity & K+ conc vs. At highest flow rate saliva has osmolarity close to plasma. * The Acinus produce initial saliva whose composition is same as plasma but duct modify the saliva by reabsorbing Na+ and cl- and secreting K+ and HCO3.( Aldosterone act on ductal cell reabsorption of Na+ and secret K+ ) * Duct is relatively impermeable to water hypotonic saliva * Parasympathetic stimulation is through facial nerve VII and glossopharyngeal nerve IX production of saliva (receptors are muscarinic and 2nd messenger is IP3 where as sympathetic stimulation also cause production of saliva but receptors are and 2nd messenger is cAMP.
* SWALLOWING REFLEX coordinated in medulla. vs. vagus & glossopharyngeal nerve carry info to & from the medulla. * During swallowing beathing inhibit, nasopharynx close, perstalsis begin, larynx elevate (glottis close), upper esophageal sphincter relax (gravity accelerate the movement). * At rest intraesophegeal P is < than atmospheric P, Intrathoracic P can be measured by baloon catheter. * Primary peristalsis create just behind the food and secondary peristalsis clear the esophagus. * Lower esophageal sphincter relax (via vagus nerve neurotransmitter is VIP) at the same time Orad stomach relax (receptive relaxation) CCK participate in it by increasing dispensability of Orad stomach. * Gastric reflux ---- occur when tone of esophageal sphincter or secondary peristalsis does not clear food particles. * Achalasia ---- when lower esophageal sphincter does not relax, in turn food accumulates in esophagus. * Orad region ---- contain Oxyntic gland vasovagal reflex relax Orad region. (Oxyntic gland secrete Hcl and Intrinsic factor) * Caudad region ---- contraction, mixing occur and food propel to doudenum. * MIGRATING MYOELECTRIC COMPLEX :* Are contraction that occur at 90 min interval during fasting which clear stomach. Motilin cause those contraction. * Gastric emptying is fast when contents are isotonic and is slow when contents are hypertonic or fatty. * H+ in doudenum inhibit gastric emptying by direct neuronal reflex via GI plexus. * Segmental contraction mixing of contents in orad and caudad direction but no net movement of food occur . * Peristaltic contraction coordinated by enteric nervous system & propel food downward.( contraction behind bolus and relaxation in front of bolus )
* Gastroileal reflex deliver intestinal content in colon. Reflex mediated by ANS and gastrin. * Haustra is a sac like segment appear following segmental contraction of colon (during mixing the colon content). * Once rectum is filled about 25% cause urge to defication (it can be prevent by voluntarily by external sphincter). * Valsalva maneuver :- voluntary increasing of intraabdominal P by expiring against closed glottis. * Food in stomach gastro colic reflex frequency of mass movement. * Parasympathetic activity cause rapid gastrocolic reflex whereas CCK & Gastrin slows down the gastrocolic reflex. * Gastrocolic reflex : Is food in stomach which the motility of the colon and frequency of mass movement.
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------GI SECRETION
CONTENTS
STIMULATED BY
INHIBITED BY
--------------------------------------------------------------------------------------------------------------------------------------Saliva
Gastric
HCO3 , K+ Hypotonic amylase (starch) Lingual lipase (triglycerides) Kellikrein HCl
Pepsinogen Intrinsic factor
IP3 parasympathetic (imp) cAMP sympathetic ( )
Gastrin, Ach, Histamine (H2) via cAMP
Sleep Dehydration Atropine (anticholinergic)
PH of stomach Chyme in doudenum Atropine, Cemetidine, vagotomy, omeprazole
parasympathetic
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------CELL TYPE
SITE
PRODUCT
STIMULUS FOR SECRETION
--------------------------------------------------------------------------------------------------------------------------------------Oxyntic (parietal cell)
Fundus
Chief cell (peptic cell)
Fundus (Body)
G cell Mucous cells
Antrum Antrum
HCl Intrinsic factor Pepsinogen (convert to pepsin at low PH) Gastrin mucous, pepsinogen
Gastrin, Histamine, Ach (vagal) Ach (vagal stimulation) see above Ach (vagal stimulation)
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Gastric Secretions --- HCl is secreted by parietal cell into lumen of stomach and HCO3 absorbed in blood stream and HCO3 absorbed in venous blood (Alkaline Tide) later it secreted back into the lumen of the GI tract via pancreatic secretion to neutralize H+ in small intestine. Fig:
* Chief cells secret Pepsinogen in the form of zymogen granules. * When stomach is empty its PH is < 3.0 inhibition of gastrin release, which further inhibit H+ secretion via somatostatin. * Chyme in the doudenum inhibit H+ secretion directly or via hormone GIP (release by fatty acid in stomach) & Secretin (release by H+ in duodenum). * In gastric ulcer H+ is lower than normal and Gastrin is * In duodenal ulcer H+ is higher than normal, Gastrin is high and Gastric perital cells are because of gastrin mediated growth. * Zollinger Ellison $ --- Gastrin secreting tumor of pancreas H+ secretion & is not subject to - ve feedback inhibition of H+. * In vomiting H+ is lost and results into Metabolic Alkalosis (arterial Blood become Alkaline) ---------------------------------------------------------------------------------
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD.
* PANCREATIC SECRETION :* Pancreatic juice is high in vol having same Na+, K+ conc as plasma where as HCO3 conc is higher than plasma, and Cl- conc is lower than plasma. * Pancreatic juice has isotonicity. It contain lipase, amylase, protease. * Aqueous component is varies with flow rate. * Na+, K+ conc is not effected by flow rate ( vs. saliva ) * At low flow rate HCO3 is low and Cl- is high where as At high flow rate HCO3 is higher and Cl- is low. * The Acinar cell produce initial pancreatic juice Na+ and Cl-, than Ductal cell modified it by secreting HCO3 and absorbing Cl- (HCO3 - Cl exchange). Pancreatic duct is permeable to H2O so make it isosmotic. * Regulation of Pancreatic secretion :- It is regulated by secretin and CCK. * Secretin acts on pancreatic ductal cell HCO3 secretion (via cAMP) where as CCK acts on Pancreatic Acinar cell enz secretion (via IP3). * Ach (via vagal reflex) stimulate enz secretion by Acinar cell in response to H+, small peptide, AA, fatty acid in duodenum. * Cystic Fibrosis --- Defect in Cl channel because of mutation in the Cystic fibrosis Transmembrane conductance (CFTR) gene Which results into deficiency of pancreatic enz mal absorption (statorrhea). ----------------------------------------------------------------------------------------------------BILE SECRETION AND GALL BLADDER:* Bile contain bile salts, phospholipids, cholesterol, bile pigment(bilirubin). * Bile salt are Amphiphatic having hydrophobic and hydrophilic portion. * In water bile salt orient them selves around droplet of lipid and keep the lipid disperse in solution (emulsified). * Bile salt form Micelles by covrering one fatty acid and two monoglycerides; pointing there hydrophilic portion into the aqueous solution to make it soluble for absorption. * Bile is produce by hepatocytes continuously (chloretic agent increase bile formation). * primary bile acid (cholic acid and chenodeoxycholic acid) is syn in hepatocytes than conjugate it to glycine and Taurine to form the respective bilesalt. * Intestinal bacteria convert primary bile acid to secondary bile acid (deoxycholic acid and lithodeoxycholic acid). * Gall bladder concentrate the bile by NaCl and HCO3 reabsorption where as water reabsorbs isosmotically. CONTRACTION OF GALL BLADDER :* CCK cause contraction of gall bladder & relax sphincter of Oddi. vs. Ach cause only contraction of Gall bladder. * Terminal ileum absorbes conjugated bile acid with Na+ by sec active transport. * Bile depletion cause statorrhea, bile pool depletion and Anemia, for e.g. Due to ilieal resection or diseased ileum. ---------------------------------------------------------------------------------------------------DIGESTION AND ABSORPTION : CARBOHYDRATE -- Absorbs only in the form of monosaccharide (glucose, galactose, fructose). * Amylase (salivary and pancreatic) hydrolyze 1,4 glycosidic bond in starch & yield oligosaccharides maltose, maltriose, & limit dextrin which is further hydrolyze to yield glucose, galactose & fructose by enz maltase, dextranase & sucrase (brush border enz). * Lactase, Trehalase also yield monosaccharide form disaccharides. * Glucose and galactose absorbs with Na+ as a sec active transport, where as Na - K pump at basolateral side maintain IC Na+. If this pump is poisoned Glucose, galactose absorption stops. * Glucose, Galactose entered the intestinal cell by Na+ dependant Sec active transport (Cotransport) later it entered blood by facilitated diffusion. * Fructose absorption in the intestinal cell occur by facilitated diffusion ( so can not absorb against its gradient). * Lactose intolerance occur when brush border lactase is or absent lactose cant be absorb H2O remains in lumen results in osmotic diarrhea.
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KICK THE BOARDS “USMLE STEP 1”
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PROTEIN -- Absorbs as a AA, Dipeptide and Tripeptide in intestinal cell. * Endopeptidase hydrolyze interior peptide bond, vs. Exopeptidase hydrolyse one AA at a time from C terminal . * Pepsin secreted as pepsinogen from Chief cells H+ converts it into pepsin. * PH for pepsin is 1 – 3, PH more than 5 inactivate pepsin as in duodenum. Pepsin is not essential for protein digestion * Pancreatic protease are secreted in inactive form which is activated by brush border enz. eg Tripsinogen is converted to Trypsin (active form) by Enterokinase in small intestine. * Dipeptide and Tripeptide must hydrolyse by cytoplasmic peptidase to AA prior to enter into the blood. * Free AA, Dipeptide and Tripeptide absorb with Na+ as sec active transport than AA enters blood by facilitated diffusion. * Dipeptide & Tripeptide absorbs faster than free AA due to 4 separate carriers for acidic, basic, neutral & Imino AA absorption. * Pancreatic protease degrade each other and also absorbed along with dietary protein. LPIPDS -- Absorbs as fatty acid, monoglycerides & cholesterol in the form of micelles. (Glycerol is hydrophilic & is not contain in micelles) * Lingual Lipase digest some lipids, stomach breaks lipid into droplets and intestinal bile emulsify it. * Pancreatic lipase, cholesterol ester hydrolase & phospholipase A2 hydrolyze lipids into fatty acid, monoglyceride & chlesterol. * Intestinal cells reesterified Triglycerides, phospholipids with cholesterol and apoprotein form chylomicron & than chylomicron transported out of cell by exocytosis in the lymphatics later chylomicron added to the blood via thoracic duct. * Abetalipoproteinemia is failure to synthesize Apoprotein results in inability to transport Chylomicron out of cell. (apoprotein is one of the constituents of chylomicron). * Hyper secretion of gastrin H+ secretion PH in duodenum Inactivate pancreatic lipase Statorrhea. ABSORPTION OF ELECTROLYTE AND WATER :- Occur by cellular and paracellular routes. Tight Junction are Tight (impermeable) junction present in epithelium of colon. Leaky (permeable) junction present in epithelium of small intestine and gall bladder. NaCl absorption ------- 1. Passive diffusion (Na+ channel) 3. NaCl cotransport.
2. Na+ glucose, Na+ AA co transport. 4. Na+ - H+ exchange.
* In colon Na+ channel are stimulated by Aldosterone. * Na+ - K pump IC Na+ conc on basolateral side. * Cl- absorption accompanies Na+ absorption through out the GI tract by -- 1. NaCl co transport 2. Cl - HCO3 exchange 3. Cl diffuse passively by paracellular route. * K+ absorbs by passive diffusion (via paracellular route in small intestine) where as K+ secreted actively by aldosterone in colon In diarrhea K+ secretion is in colon hypokalemia. * H2O absorbs in small intestine and gall bladder osmotically. Where as colon is less permeable to water. SECRETION OF ELECTROLYTE AND H2O :- Secretive mechanism is located in Crypt. vs. absorptive mechanism is in Villi. * Cl is primary ion secreted in intestinal lumen through Cl- channel (via cAMP) and Na+ follow Cl- where as water follow them. * Cholera toxin some E- Coli toxin activate adenylate cyclase at the basolateral mem of the crypt IC cAMP Cl secretion Na+ and H2O follow Cl- Diarrhea. VITAMINS :- Fat soluble vit absorbs along with lipid and water soluble vit absorbs with Na+ cotransport where as VitB12 together with Intrinsic factor absorbed in ileum. * Ca++ :- Ca++ absorption depend on active vit D (1,25 dihydroxycholecalciferol). ( vit D cause Rickets and Osteomalacia ) * Iron :- Iron absorbes as heme iron ( bound to hemoglobin or myoglobin ) or as a free Ferrous (Fe++). In Intestine cells Heme iron broke down to release iron which bind to Apoferritin and transport to blood than In blood it bound with Transferrin which take iron to liver and store it. (Iron deficiency is the most common cause of anemia) ------------------------------------------------------------------------------------
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KICK THE BOARDS “USMLE STEP 1”
Prepared by Dr. IRFAN MIR MD. RENAL AND ACID BASE PHYSIOLOGY
* TBW -- 60% of body wt. ( TBW vol is measured by Titrated H2O or D2O) * ICF -- 2/3 of TBW and is measured by TBW - ECF. ( it contain K+, Mg++, Protein, Inorganic ph, ATP etc) * ECF --1/3 of TBW and is measured by sulfate, inulin, or manitol. (it contain Na+, Cl-, HCO3). * Plasma -- ¼ of ECF or 1/12 of TBW & is measured by radioiodinated serum albumin RISA or evan blue.(it contain Albumin and Globulin etc) * Interstitial fluid --- ¾ of ECF ( ¼ of TBW ) and is measured by ECF - Plasma. * Fluid Compartment -- is measured by vol = amount injected - amount excreted / conc in plasma. ------------------------------------------------------------------* RBF (renal blood flow) is 25% of cardiac out put. * RBF remain constant over the range of arterial BP from 100 - 200 mmHg (auto regulation). * RPF (renal plasma flow) measured by PAH clearance because PAH is both filtered and secreted by renal tubules. * Rena clearance can be measured by C = UV/P RPF = c PAH = [U] PAH V / [P] PAH * GFR is 20% of renal plasma flow (RPF) 125ml/min. GFR = [U] inulin V / [P] inulin. * GFR is measured by Inulin clearance because Inulin is filtered but not reabsorbed or secreted by renal tubules. * Both BUN and Plasma Creatinine as GFR . * Filtration Fraction is the fraction of RPF that filter across the glomerular capillaries ( it is 0.20). thus 20% of RPF is filtered. Filtration Fraction = GFR / RPF GFR = Kf [ ( PGc - PBc) - ( Gc -
* GFR can be expressed by Starling equation.
Bc) ]
* PGc : -- is constant along the length of capillaries. It by dilatation of afferent arterioles & by constriction of efferent arterioles. * PBc : -- by constriction or blockade of ureter GFR. * Gc :-- along the length of glomerular capillaries. It by in protein conc GFR. * Bc : -- is zero small amount usually absorbs * NaCl and Mannitol donot cross cell mem and confined to ECF, * More water than salt lost during sweating. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------TYPE EXAMPLE ECF Vol ICF Vol ECF Osmolarity Hct, Serum Na+ ------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Isosmotic Vol Expansion Isotonic Nacl infusion No change No Change Hct , Na - Isosmotic Vol Contraction Diarrhea No change No change Hct , Na - Hyperosmotic Vol Contraction Sweat, fever, Diabetes Insipidus Hct (RBC shrunk) Na+ . Hyperosmotic Vol Expansion NaCl intake Hct ,Na+ . Hyposmotic Vol Expansion SIADH Hct (RBC swell), Na+ Hyposmotic Vol Contraction Adrenocortical insufficiency (loss of NaCl) Hct, (RBC swell) Na+ . ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* TRANSPORT MAX CURVE FOR GLUCOSE :- Plasma glucose conc of < 300 mg/dl can be absorbed by proximal tubule through Na - glucose co transport. * Threshold at which glucose first appear in the urine is approx 300 mg/dl. * SPLAY is the region of glucose curve b/w Threshold and transport max. (300-350mg/dl) * At 300 - 350 mg/dl --- spilling of glucose occur in urine before saturation or (Tm) Transport maximum. * Tm CURVE FOR PAH :- PAH filtration as PAH plasma conc .
* Secretion of PAH from Peritubular capillaries into tubular fluid occur in proximal tubule. * PAH secretion when plasma conc once carriers become saturated it stops further in secretion due to Tm. * RPF is measured at plasma PAH conc below the Tm (Transport max). * Relative Clearance: PAH > K+ > inulin > urea > Na+ > glucose > AA > HCO3-. * Na+ REGULATION: Na+ in the tubular fluid (TF) in Bowman space equals that in plasma (P) is said to be TF/ PNa+ = 1.0 * If TF/PNa+ is < 1 Net Reabsorption of solute occur dilution of TF. * If TF/PNa+ is > 1 secretion of solute occur produce concentrated TF.
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KICK THE BOARDS “USMLE STEP 1”
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* Only 1% of filtered Na+ is excreated. * Na+ is reabsorbed by Co transport with glucose, AA, ph, lactate, K+ in proximal tubule. * Na+ is reabsorbed also by Counter transport as Na+ - H+ exchange in PT. * Na+ absorbed with Cl- in middle and late PT. (total of 67% of Na+ reabsorbed in PT) * In Thick ascending limb of Loop of Henle 20% of Na+ reabsorbed as Na+ - K+ - 2Cl- Cotransport also called diluting segment and is impermeable to H2O (loop diuretics act here). * Distal tubule and Collecting duct together reabsorbe 12% of filtered Na+. * Early Distal tubule is Cortical Diluting segment reabsorb Na+ by Na+ - Cl- Co transport. (Thiazide act here). * Principle cell reabsorb Na+ & secrete K+ in late distal tubule (DT) & collecting duct. (Aldosterone/ ADH act here) * Intercalated cell secrete H+ & reabsorb K+ in late DT & collecting duct. (Aldosterone also act here to secrete H+). * Starling forces in peritubular capillaries (due to or in protein conc) or in proximal tubular reabsorption.
* K+ REGULATION :- K+ is filtered, secrete & reabsorbed by nephron to achieve K+ balance. * TF/PK+ = 1 in Bowman space. * PT reabsorb 67% of K+ alonge with Na+ and H2O. * Thick ascending limb of Loop of Henle reabsorb 20% of filtered K+ as Na+ - K+ - 2Cl- Cotransport. * Distal Tubule and collecting duct either reabsorb or secrete K+ depend on dietary intake. SHIFT OF K+ b/w ECF AND ICF -----------------------------------------------------------------------------------------------------------------------------------------------------------------------Causes of K+ shift out of cell ( hyperkalemia) Causes of K+ shift into the cell (hypokalemia) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------* Insulin Deficiency * Insulin * adrenergic antagonist * agonist * Acidosis ( via H+ - K+ exchange ) * Alkalosis ( via H+ - K+ exchange) * Hyperosmolarity (H2O out of cell K+ follow) * Hyposmolarity (H2O flow into the cell K+ follow) * Na+ - K+ pump inhibitor * Excersize * Cell lyses ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
EFFECT OF DISTAL K+ SECRETION --------------------------------------------------------------------------------------------------------------------------------------Causes of distal K+ secretion Causes of distal K+ secretion -----------------------------------------------------------------------------------------------------------------------------------------------------------------------* High K+ diet * Low K+ diet * Hyperaldosteronism * Hypoaldosteronism * Alkalosis * Acidosis * Thiazide * K+ sparing Diuretics * Loop diuretics * Renal failure * Luminal Anion --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Urea Regulation : 50% of urea reabsorb passively in PT. Other segment are impermeable to urea. * ADH urea permeability of inner medullary collecting duct which contribute urea recycling in the medulla. * Phosphate Regulation : 85% of phosphate reabsorb in PT as Na+ - phosphate Cotransport. Where as 15% excreted. * PTH Inhibit phosphate reabsorption phosphaturia & urinary cAMP. ( PTH also bone resorption ) * phosphate is urinary buffer for H+ excretion of H2PO4 (titrableacid). * Ca++ Regulation : 90% of Ca++ reabsorbed in PT and Thick ascending limb of Loop of Henle. * Loop diuretics cause Ca++ excretion by inhibiting Na+ reabsorption. ( Tx of hypercalcemia ) * Thiazide Ca++ excretion by reabsorbing Ca++ in distal tubule ( Tx of Hypercalciurea ). * DT and Collecting duct reabsorb 9% of Ca++ actively. * PTH Ca++ reabsorption in DT. * Mg++ Regulation : Reabsorb in PT, Thick ascending limb and DT * In Thick ascending limb Mg++ and Ca++ compete for reabsorption. * Mild in Mg++ stimulate PTH secretion Ca++ reabsorption. * Severe in Mg++ inhibit PTH secretion Mg++ reabsorption.( also Phosphate reabsorption )
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KICK THE BOARDS “USMLE STEP 1”
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* CONC AND DILUTION OF URINE :* Corticopapillary osmotic gradient : * Is the gradient of osmolarity from cortex ( 300 mOsm /L) to papilla (1200 mOsm /L) & is comprise primarily of NaCl & urea. * Vasa Recta (capillaries of Loop of henle) maintain the corticopapillary gradient by serving as osmotic exchanger. * Thick Ascending loop of henle reabsorbe Na+ - K+ - 2Cl by cotransport & is permeable to H2O. [ TF/Plasma osmo = <1 ] * Early distal tubule is cortical diluting segment and is impermeable to H2O. * In late distal tubule H2O permeability by ADH. Here H2O reabsorb normally until TF/Plasma Osmo = 1 * In collecting duct H2O permeability by ADH. Here H2O reabsorb normally untill TF/Plasma Osmo >1 . HORMONES THAT ACTS ON KIDNEY: --------------------------------------------------------------------------------------------------------------------------------------------------------------------------Hormnes
Stimulus for secretion
Time course
Mech of action
Action on kidney
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------PTH
Plasma Ca++ mild in Mg++
Fast
Adenylate Cyclase cAMP (at basolateral side)
ADH
Plasma Osmolarity Blood vol Blood vol (via renin AT) Plasma K+
Fast
Adenylate cyclase V2 Receptors New Protein Synthesis
ANF
Atrial Pressure
Fast
Angiotensin
Blood vol (via renin)
Fast
Aldosterone
Slow
Guanylate cyclase cGMP IP3 mech
ph reabsorption (PT) Ca++ reabsorption (DT) Stimulate 1 hydroxylase in PT H2O permeability in late DT & collecting duct (principle cell) Na Reabsorption in DT- Principle cell K secretion in DT - Principle cell H+ secretion in DT - Intercalated cell GFR, Na+ reabsorption
Na+ - H+ exchange in PT (stimulate Aldosterone synthatase) HCO3 reabsorption in PT ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
ACID BASE BALANCE : * Buffer prevent changes in the pH when H+ ions are added or removed. ( Buffer is most effective in the linear portion of the titration curve.) * Buffer are more effective with in 1.0 pH unit of the pK. * Major EC buffer is HCO3. (pK of CO2/ HCO3 buffer is 6.1) * Minor EC buffer is Phosphate (PK of H2PO4 /HPO4 2 buffer is 6.8) * Major IC buffer is Hg. Deoxyhemoglobin is Better buffer than Oxyhemoglobin at physiologic pH. * Minor IC buffer is organic Phosphate (AMP, ADP, ATP, 2,3 DPG) * When pH of the solution is equal to pK than there are equal conc of HA- and A-. * PH = pK + log [A-]/ [HA-] . (where A- is base of the buffer and HA- is acid of the buffer) RENAL ACID BASE : * Filtered HCO3 reabsorbs in proximal tubule in two steps * PCO2 HCO3 Reabsorption ( because IC H+ is ) * PCO2 HCO3 Reabsorption ( because IC H+ is ) * ECF vol contraction HCO3 Absorption (contraction Alkalosis) and produce acidic urine. * ECF vol expansion HCO3 Reabsorption . * Angiotensin II stimulate Na+ H+ exchange HCO3 reabsorption. (Contributing to Contraction Alkalosis) ----------------------------------------------------------------------------------------------* H+ secrete in the lumen by H+ - ATPase and resultant HCO3 is reabsorbed. * Secreted H combine with filtered HPO4 H2PO4 (titrable acid). This Process results into net excretion of H+ in urine. * Another mech for excreting H+ is NH3 Production in renal cell from glutamine. ( NH3 production in Acidosis which favor H+ excretion ) H+ + NH3 NH4+ excreted in urine (diffusion trapping)
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KICK THE BOARDS “USMLE STEP 1”
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ACID BASE DISORDER: --------------------------------------------------------------------------------------------------------------------------------------DISORDER
CO2 + H2O
H
+ HCO3
Resp Compensation
Renal Compensation
--------------------------------------------------------------------------------------------------------------------------------------Metabolic Acidosis
H+ excretion HCO3 reabsorption Metabolic Alkalosis Hypoventilation HCO3excretion Respiratory Acidosis None H+ excretion HCO3 reabsorption Respiratory Alkalosis None H+ Excretion HCO3 reabsorption ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------* RULE : CO2 goes up HCO3 goes up CO2 goes down HCO3 goes down. ( Directly proportional relationship).
Hyperventilation
Normal Serum Anion Gap is 10 - 16 mEq / L. ( Serum Anion Gap = [Na+] - [Cl-] - [HCO3-] ) * Synthesis of Glucose (gluconeogenesis) during prolong fasting also occur in kidney. * H+ Excreted in urine as H+ + HPO4 -2 H2PO4 (Titrable acid) H+ + NH3 NH4+ (diffusion trapping) *
------------------------------------------------------------------------------------------------------------------------RESPIRATORY PHYSIOLOGY * LUNG VOLUMES : 1. Tidal Vol -- is the vol inspired and expired with each normal breath. 2. Inspiratory Reserve Vol (IRV) -- is the vol that can be inspired over the tidal vol eg during exersize. 3. Expiratory Reserve Vol (ERV) -- is the vol that can be expired after expiration of the tidal vol. 4. Residual Vol (RV) -- Vol that remains in the lung after max expiration. ( cant be measure by spirometery ). * Anatomic Dead space -- Vol of conducting airway it is 150 ml normally. (measured by Fowler’s Method ) * Physiologic Dead space -- vol of the lung does not eliminate CO2 normally or due to dis. ( measured by Bohr’s Method ) * Minute Ventilation = Tidal Vol Breath / min * Alveolar ventilation = Tidal Vol Dead space Breath / min * LUNG CAPACITIES : 1. Inspiratory Capacity = Tidal Vol + Inspiratory Reserve Vol. 2. Functional Residual Capacity (FRC) = Expiratory Reserve Vol + Residual Vol 3. Vital Capacity = Tidal Vol + Inspiratory Reserve Vol + expiratory Reserve Vol 4. Total Lung Capacity = Tidal Vol + IRV + ERV + RV.
(can not measured by spirometery)
* Forced Expiratory Vol (FEV): Is air expired in one Second after Max Inspiration. It is 80% of forced vital Capacity. FVC. FEV / FVC = 0.8 * In restrictive Lung Dis ( Fibrosis ) both FEV and FVC is reduced. * In Obstructive Lung Dis ( asthma ) FEV reduces more than FVC. * MUSCLE OF INSPIRATION : Diaphragm (normally) External Intercostal Muscle Accessory Muscle ( during exercise )
* MUSCLE OF EXPIRATION : Passive (normally) Abdominal & Internal Intercostal muscle ( during exercise )
* COMPLIANCE :-The extent to which lung expand (stretchability) for each unit in Transpulmonary P is called the Compliance. Compliance Stretchability where as compliance stretchability. ( Compliance measures stiffness of the lung ) ( Change in Intrapleural P during inspiration is used to measure dynamic compliance of the lung )
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KICK THE BOARDS “USMLE STEP 1”
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--------------------------------------------------------------------------------------------------------------------------------------* Causes of Lung Compliance * Causes of Lung Compliance --------------------------------------------------------------------------------------------------------------------------------------High Expanding Pressure Pulmonary venous return Fibrosis Lack of surfactant
Emphysema ( Elastic fiber) Age
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------* Under equilibrium condition lung have a tendency to collapse which is exactly balance by tendency of chest wall to spring out. * HYSTERESIS :- Is inflation of the lung follow different curve than deflation of the lung. * Compliance of the lung chest wall system is less than the lung alone or chest wall alone. * In Emphysema lung compliance is so FRC too. This change disturb the lung chest compliance system, so the lung chest wall system seek for higher FRC in order to balance these two forces again. This is the reason pt develop barrel shape chest to provide new Vol to lung with results into O2 diffusion. * SURFACE TENSION OF ALVEOLI AND SURFACTANT : * Tendency to collapse alveoli is directly proportional to the surface tension and inversely proportional to alveolar radius called Laplace Law . ( large alveoli has low tendency to collapse than smaller alveoli ). * Surfactant lines the alveoli and reduce the tension compliance. * Surfactant is made by Type II alveolar cells consist of Dipalmitoyl Phosphatidyl Choline. * Neonatal RDS cause by lack of surfactant Atelactasis (difficulty in reinflation due to compliance) Hypoxemia (V/Q mismatch).
* AIRWAY RESISTANCE :- Airflow is directly proportional to pressure difference of the mouth and alveoli and inversely proportional to airway resistance . (Airflow) Q = P/R ( where P is pressure gradiant and R is Airway Resistance) * Airway Resistance (R) is describe by Poiseuille’s Law . R = 8nl / r4 Where n is viscosity of the inspired air, l is length of airway, and r is radius of airway. * Factor that change Airway Resistance : * Parasym stimulation, Irritants, Slow reacting subs of anaphylaxis (constricts airway) radius and resistance * Sympathetic stimulation dilates airways Radius and Resistance (via 2 receptors). * Lung Vol exert more traction (pulling force) & airway resistance. Lung Vol exert less traction & airway resistance
vs.
For example in Asthma pt learn to breath at high lung vol to off set the high resistance.
* Viscosity & Density changes the resistance to air flow : If density of gas resistance to airflow If density of gas resistance to airflow (breathing low density gas like helium) * Medium size bronchi are major site of resistance. * Small size airway do not offer resistance because of parallel arrangement. -----------------------------------------------------------------------------------------------
(eg deep sea diving)
BREATHING CYCLE :- ( At rest before inspiration begin) 1. At Rest --- Alveolar P equals atmospheric P ( alveolar P is said to be zero ). Intrapleural P is - ve ( can be measured by baloon catheter in esophagus ) where as Lung vol is FRC. 2. During Inspiration -- Inspiratory muscles contract thorax Vol to . P gradient cause air to flow into the lung. Intrapleural P become more - ve and lung Vol by 1 tidal vol (+ FRC). 3. During Expiration --- Alveolar P become greater (+ ve) than atmospheric P. Intrapleural P return to its resting value during normal expiration (passively). During forced expiration Intrapleural P become +ve Lung vol return to FRC before another cycles begin. ( In COPD airway resistance is & pt expires slowly with pursed lip to prevent airway collapse which occur with forced expiration )
* Gas Exchange :- * Diffusion of gases such as O2 and CO2 depends in the partial P difference across the mem and area available for diffusion. ( Can be measured by Dalton’s Law Partial P = Total P Fractional concentration ).
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KICK THE BOARDS “USMLE STEP 1”
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* About 2% of Cardiac output bypass pulmonary circulation because of physiologic shunt that’s why mixture of the venous blood makes PO2 of arterial blood slightly less than alveolar air. * Solubility of O2 in the blood is 0.3 ml/100ml of blood . Blood gases value in normal conditions: --------------------------------------------------------------------------------------------------------------------------------------------------------------------------Gas
Dry Inspiration
Humid Inspiration
Alveolar Air
Sys Arterial Blood
Mixed Venous Blood
--------------------------------------------------------------------------------------------------------------------------------------PO2 160 mmHg 150 mmHg (due to H2O in air) 100 100 % (slightly less) 40 mmHg PCO2 0 40 mmHg 40 mmHg 46 mmHg ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* Perfusion limited exchange --- When gas equilibrate early along the length of pulmonary capillaries the partial P of arterial blood become equal to partial P of alveolar air. * Diffusion limited exchange --- When the gas does not equilibrate fully by the time blood reaches the end of the pulmonary Capillaries the partial P of arterial blood is less than that of alveolar air . * Diffusion of O2 from alveolar air to pulmonary capillaries bed is usually perfusion limited but become diffusion limited in dis. Eg In Fibrosis diffusion of O2 because of thickening of the alveolar mem diffusion distance. Where as in Emphysema diffusion of O2 because surface area for diffusion is . -----------------------------------------------------------------------------------------------O2 TRANSPORT : * Hg contain 4 subunit 2 and 2 ( each subunit contain heme moiety which is iron containing porphyrin ) . * Ferrous (Fe2+) state of iron bind O2 Where as ferric (Fe3+) state of iron is methemoglobin and does not bind O2. * In fetal Hg chain is replaced by chain. * O2 affinity of fetal Hg is higher than adult because 2,3 diphosphoglycerate (DPG) bonds less avidly to fetal Hg. ( that is why O2 movement from mother to fetus is facilitated ). Hg O2 DISSOCIATION CURVE : * At PO2 of 100 mmHg Hg is almost 100% saturated. * At PO2 of 40 mmHg 75% of Hg is saturated. * At PO2 of 25 mmHg 50% of Hg is saturated. * The affinity of 4th O2 molecule is very high. * Because the curve is almost flat in PO2 range from 60 - 100 mmHg, the human can tolerate change in atmospheric P without compromising the O2 carrying capacity of Hg. CHANGE IN O2 DISSOCIATION CURVE : 1. Shift to the right --- Affinity of Hg for O2 P50 . (Causes are PCO2, PH, Temp, 2,3DPG). * Adaptation of chronic Hypoxemia (high altitude) 2,3DPG which bind to Chain to facilitate unloading of O2 in tissue. By the affinity of O2 . * PCO2 and PH the affinity of Hg for O2 & facilitating the unloading of O2 in tissue as in exercise. ( Bohr’s Effect ) 2. Shift to the Left --- Affinity of Hg to the O2 P50 unloading of O2 in tissue is more difficult . * Causes are PCO2, PH, Temp, 2,3DPG. CO2 TRANSPORT : CO2 carried to the lung in 3 Forms. 1. HCO3- ( 90% .major form ) 2. Carbaminohemoglobin ( small amount ) 3. Dissolved CO2 ( small amount ) * CO2 generate in tissue enter into venous plasma enter into RBC where CO2 combine with H2O by Carbonic anhydrase H2CO3 H+ and HCO3-. * H+ is buffered inside RBC (Deoxyhemoglobin) where as HCO3- is exchanged for Cl- by RBC (Cloride shift). * In lung all above reaction occur in reverse ( which is HCO3- enter into RBC in exchange for Cl- than HCO3combines with H+ H2CO3 which further decompose into CO2 and H2O and CO2 is diffuse out ). * Pressure and Resistance in pulmonary circulation is much lower than systemic circulation. * Cardiac output (pulmonary) is equal to systemic circulation.
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DISTRIBUTION OF PULMONARY BLOOD FLOW --- Distribution of pulmonary blood flow effect by gravity. * In supine position blood flow is uniform through out the lung where as standing position blood flow is lowest in apex. BLOOD FLOW IN LUNG ZONES : Zone 1 -- Alveolar P > Arterial P > Venous P (blood flow is lowest) -- V/Q . ( Alveolar P collapses the capillaries when arterial BP is low eg .In Hemorrhage) Zone 2 -- Arterial P > Alveolar P > Venous P (blood flow is medium). Zone 3 -- Arterial P > venous P > Alveolar P (blood flow is highest) -- V/Q .
* Hypoxia cause local vasoconstriction (Opposite effect of that in systemic circulation where hypoxia cause vasodilation) . It is imp in lung because local vasoconstriction divert blood from poorly ventilated area to well ventilated area. * In fetus pulmonary vascular resistance is very high due to generalized hypoxic vasoconstriction as a result blood flow through fetal lung is low . ( with first breath alveoli become oxygenated and vascular resistance decreases ) * Both ventilation and Perfusion is great in base than in apex. ? (very imp to understand) * Right to left shunt normally occur to a small extent because 2% cardiac output by passes the lungs. More than 2% is Usually due to congenital abnormality in arterial PO2. Where as Left to right shunt in venous PO2 (donot result in a in arterial PO2)
VENTILATION / PERFUSION RATIO : 1. Normal V/Q Ratio = 0.8 ( 0.8 when tidal Vol & pulmonary cardiac out put are normal, and it is liable for 100 mmHg of PO2 & 40 mmHg of PCO2).
2. V/Q is Zero when airway is completely blocked, Perfusion is normal and ventilation is Zero No Gas Exchange. 3. V/Q is Infinity when blood flow is blocked and ventilation is normal No Gas Exchange. * V/Q is highest ( > 1.0 ) in the apex of the lung and lowest ( 0.8 ) at the base of the lung. (imp to understand) * PO2 is greater than PCO2 in different region of lung. 1. At apex ---- PO2 and PCO2 2. At base ---- PO2 and PCO2 ---------------------------------------------------------------------------------------CONTROL OF BREATHING :1. Medullary Resp Center:Dorsal Respiratory Group control inspiration & generate basic rhythm of breathing receive input from lung via vagus & from peripheral chemoreceptor via glossopharyngeal nerve where as it send output to diaphragm via pherenic nerve . Ventral Respiratory Group control Expiration & is not active during normal breathing because Expiration is passive .
2. Apneustic center ------------- located in the lower pons . It stimulate inspiration more deeper and prolongs Inspiratory gasp. (Apneusis) 3. Pneumotaxic Center --------- located in the upper pons. It inhibit inspiration therefore regulate inspiratory Vol and rate. 4. Cortex ------------------------- Breathing can be under voluntary control. ---------------------------------------------------------------------------------------CHEMORECEPTORS FOR O2, CO2, & H+ :1. Central Chemoreceptors of the medulla is sensitive to PH of CSF. * H+ does not cross the BBB but CO2 does. So when CO2 enter CSF combine with H2O H2CO3 H+ + HCO3(by carbonic anhydrase) than liberated H+ can act directly on central chemoreceptors. ( that’s why or in CO2 cause change in breathing). 2. Peripheral chemoreceptors present in Carotid and Aortic bodies. (stimulate by PO2, PCO2, H+) * When Partial PO2 falls < 60 mmHg breathing rate by peripheral chemoreceptors. * When PCO2 in breathing rate. * H+ ion stimulate carotid bodies chemoreceptors directly and is independent of PCO2 . eg Metabolic Acidosis the breathing rate ( where PCO2 is low). OTHER RECEPTORS THAT CONTROL BREATHING RATE : 1. Lung Stretch Receptors ( Hering Breuer Reflex ) stimulate by distention of lung in breathing rate. 2. Irritant Receptors located in b/w airway epithelial cells. It stimulate by noxious stimuli eg ammonia, smoke etc. 3. J Receptors located in alveolar wall close to capillaries it stimulated by capillaries engorgement as in LHF Rapid shallow breathing. 4. Joint and Muscle Receptor Breathing during (early) exercise.
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INTEGRATED RESPONSE OF RESPIRATORY SYSTEM DURING EXERCISE : * O2 consumption and CO2 production * ventilation rate * No change in arterial PO2 and PCO2 where as Venous PCO2 . * PH stays normal during moderate exercise where as PH during strenuous exercise due to lactic acid production. * Pulmonary blood flow . V/Q rate more evenly distributed through out lung ADOPTATION TO HIGH ALTITUDE : * Alveolar PO2 and Arterial PO2 also . * Ventilation rate . * Arterial PH ( Respiration cause Alkalosis ) * Hg conc ( because erythropoietin production ) * 2,3 DPG conc ( facilitate unloading of O2 in tissue ). * Hg O2 dissociation curve shift to the right side (Bohr’s effect), affinity of Hg for O2 and facilitate unloading O2. * Pulmonary vascular resistance (vasoconstriction). ----------------------------------------------------------------------------------------------------------------CARDIOVASCULAR PHYSIOLOGY * Stress Vol is the blood in systemic arteries which are thick walled. * Arterioles are the site of high resistance and is innervated by autonomic fibers. * Capillaries comprise of largest total cross sectional area and surface area. * Unstress Vol is the blood in systemic veins and have lowest P. * Velocity of blood flow is directly proportional to blood flow & inversely proportional to cross sectional area. v = Q/A * Blood flows from high P to low P & is inversely proportional to resistance of the blood vessel. Q = P/R (Q= Flow, A= area) * Resistance is directly proportional to the blood viscosity & length of the vessel and inversely proportional to the 4th Power of the vessel radius ( Poiseuille’s Law ). R = 8l / r4 ( is viscosity and l is length of vessel ) * Renolds No: Renolds No predict whether flow is laminar or turbulent. As renold No the tendency of turbulence. Blood viscosity ( due to anemia, Hematocrit) the Renold No Turbulence. ( produce audible bruits ) Blood viscosity (eg. in narrowing of vessel, polycythemia) the renold No turbulence. (produce bruits ) * Capacitance ( compliance ) describes the distensibility of the blood vessels & is directly proportional to Vol & inversely proportional to P. C = V/P ( V is volume where as v is flow ) * Compliance is much greater in arteries. Compliance as person ages. ( Compliance Pulse P ) * Blood flow P falls over its course due to changing resistance of vessels (that’s why P is highest in aorta than in vena cava). * Largest fall of P occur across the arterioles since arterioles are the site of the highest resistance. * Arterial Pressure is pulsatile and not constant during cardiac cycle. 1. Systolic P : is highest arterial P during cardiac cycle (heart contracts) 2. Diastolic P : is the lowest arterial P during cardiac cycle (heart relaxes) 3. Pulse P : is difference b/w systolic and diastolic P and is determined by stroke Vol ( stroke Vol Pulse P ) in capacitance (compliance) such as with aging results in Pulse P.( Compliance Pulse P ) 4. Mean Arterial P: is average Arterial P with respect to time calculated by Diastolic P + 1/3 of Pulse P. ELECTROCARDIOGRAM : P wave -- Atrial depolarization ( shows the size and thickness of atrium) PR interval -- Interval b/w atrial depolarization & ventricular depolarization. It is starts from beginning of P wave till the beginning of Q wave. (PR interval when conduction velocity is slow due to heart block). NL time 0.21 QRS complex -- is Ventricular Depolarization it also buried Atrial Repolarization. Normal time 0.12 QT interval -- is beginning of Q wave till the end of T wave. It represent entire depolarization & Repolarization of ventricle. Normal time 0.41 ( shows the size and thickness of ventricle) ST segment -- Is segment from the end of S wave till the beginning of T wave. It is isoelectric period shows entire ventricular depolarization. T wave -- is ventricle Repolarization.
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Cardiac AP: Na - K ATPase maintain ion gradient across cell mem. (AP are of longer duration in ventricle 300 m sec) Phase 0 : Up stroke, inward Na flow depolarization (at the peak of AP the mem potential is equilibrium potential for Na+). Phase 1 : Initial repolarization caused by inward Na+ flow and initial K+ outward flow ( it is brief period ). Phase 2 : Transit in inward Ca++ flow & outward K+ flow result in Plateau (outward & inward current are approx same during this period)
Phase 3 : Is repolarization in which inward Ca++ conductance and outward K+ conductance . outward K+ conductance hyperpolarize the mem (equal to K+ equilibrium potential) and than resting mem potential. Phase 4 : Resting mem potential ( inward outward current is equal ). Resting mem potential is determined by conductance to K+ and approaches K+ equilibrium potential. Sinoatrial Node (SA) : * It is Pace maker and does not have resting mem potential ( it exhibit Phase 4 Depolarization ) * AV Node and HIS Purkinji system are latent pace maker. It can over ride SA node if SA node is not functioning. * The intrinsic rate of Phase 4 depolarization (heart rate) is slower in AV node and HIS purkinji system than in SA node. Phase 4 : Slow depolarization -- inward Na+ conductance called I###. ( I### turn on by Repolarization ) Phase 0 : Up stroke of action potential cause by inward Ca++ flow ( it derive mem potential toward Ca++ equilibrium potential ) Phase 3 : Repolarization (caused by outward K+ conductance) * Phase 4 account for the pace maker activity of the SA node automaticity ( Note -- Phase 1 & 2 are not present in SA node action potential )
Conduction velocity is the time required for exitation to spread in the heart it is fastest in purkinji system and slowest in AV node (this is the reason EKG shows PR interval). Conduction velocity depend upon size of inward current during up stroke. EXITABILITY is ability of heart to initiate action potential response to inward current, during the course of action potential changes are describe as Refractory Period. 1. Absolute Refractory period : Begins with Action potential & end after Pleateau. AP cannot be elicited during this period. 2. Effective Refractory period : Slightly longer than ARP, conducted action potential can not be elicited. 3. Relative Refractory period : Period followed by ARP when repolarization is almost complete. AP can be elicited but more than usual current is required. ----------------------------------------------------------------------------------------------AUTONOMIC EFFECT ON HR & CONDUCTION VELOCITY : * Chronotropic Effect : is or of HR by or firing of the SA node. * Dromotropic Effect : is or of conduction velocity by slowing or speeding the conduction through AV node. * The Atria, SA node, and AV node have parasympathetic innervation but ventricle do not. * - ve chronotropic effect the HR by the rate of Phase 4 depolarization, the mech is in I### (in Na+ conductance). * - ve dromotropic effect the conduction velocity through AV node PR interval. * Sympathetic innervation is through out the heart. * + ve chronotropic effect the HR by rate of Phase 4 depolarization, the mech is in I### ( in Na+ conductance ). * + ve dromotropic effect the conduction velocity through AV node in PR interval. (Ventricle filling may be compromised).
----------------------------------------------------------------------------------------------MYOCARDIAL CELL STRUCTURE : * Sarcomeres is the contractile unit of myocardial cell it runs Z to Z. contain thick filament (myosin) & thin filament (actin, troponin, tropomyosin) * Intercalated disc present at Z and maintain cell to cell cohesion. * Gap Junction present at intercalated disc, and are low resistance pathway b/w cells. (account for electrical syncytium) * T tubules continuous with cell mem ( it carries action potential ) well develop in ventricle and poorly develop In atria. * The magnitude of tension develop in heart is proportional to the in IC Ca++. ( IC Ca++ Ca++ triggered Ca++ release from SR )
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* Ca++ binds Troponin C to remove inhibition of actin - myosin interaction by troponin - tropomyosin to cause contraction. * Relaxation occur when Ca++ is reaccumulated in SR by active Ca++ ATPase pump. ----------------------------------------------------------------------------------------------CONTRACTILITY ( Inotropism ) : Is ability of cardiac muscle to develop force at given muscle length. * It Can be measured by Ejection Fraction ( stroke vol / end diastolic vol ) which is normally 0.55 (55%). * Factor that Contractility are Parasympathetic by Ca++ entry into the cell ( - ve inotropic effect ) * Factor that Contractility ( + ve inotropic effect ) : 1. HR (In +ve Stair case or Bowditch Stair case in IC Ca++ occur over several beats & in Post extra systolic potentiation IC Ca++ due to accumulation )
2. Sympathetic stimulation. via Ca++ entry during plateau OR via Ca++ pump activity in SR ( phospholambam ) 3. Cardiac Glycoside ( Digitalis, Quabain ). ( digitalis Na+ - K+ ATPase IC Na+ to Inhibition of Na+ Ca++ exchange IC Ca++ ) Eventually all three the IC Ca++ contractility . LENGTH TENSION RELATIONSHIP : * It describes the effect of ventricular cell length on the strength of contraction (similar in skeletal muscle). * Preload is equivalent to End Diastolic Vol ( end diastolic vol in fiber length in developed tension ) * Afterload is equivalent to Aortic Pressure. It by Aortic P. ( Velocity of contraction by in after load ) Fig:
FRANK SRATLING RELATION SHIP : Is based on length tension relation ship. * Frank starling relation ship describes in Cardiac output (stroke Vol) that occur in response to an in venous P (end diastolic Vol ).
In other word it is a mechanism that matches Cardiac output and venous return. * Change in contractility shift Frank starling curve. Fig:
VENTRICULAR PRESSURE - VOL LOOP : * A cycle of ventricular contraction, ejection, relaxation, and refilling can be seen by combining of two curve into Pressure - Vol loop . It is constructed by Diastolic and systolic Pressure curve. Fig:
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CARDIAC AND VASCULAR FUNCTIONAL CURVE : * Change in End diastolic is major mechanism of alteration in cardiac output. * Cardiac functional curve shows frank starling relation ship for the ventricle. * Venous return & vascular functional curve shows relation ship b/w flow through the vascular sys & the right atrial P. * Mean systemic P is equal right atrial P when there is no flow in CVS. It or by or in blood Vol. * Slope of the venous return curve is determined by resistance of the vasculature. * A clock wise relationship of venous return curve indicate in TPR which results into venous return and cardiac output. Whereas counter clock wise relationship indicate TPR venous return & cardiac output. TPR venous return to heart vs. TPR venous return to heart.
* When two curve intersects each other the point is called equilibrium or steady point. * Equilibrium occur when cardiac output equals venous return. * + Inotropic agent (digitalis) cause in contractility → in cardiac output which further lowers right atrial P . ( this is exactly opposite of - ve Inotropic drug ) * or in Blood Vol or in venous return and cardiac output. It shows shift of curve. Fig:
CARDIAC O2 CONSUMPTION : by afterload , size of heart, contractility, HR, ( remember after load is by aortic P) Cardiac output = stroke Vol HR (can also be measured by Flick's principle CO = O2 consumption / [O2] pulmonary vein - [O2] pul artery) Stroke Work = Stroke Vol Aortic P * Stroke work is work done by heart and fatty acid is primary source of energy for stroke work. ---------------------------------------------------------REGULATION OF ARTERIAL PRESSURE : * FAST --- Neurally mediated, Baro receptor (stretch receptor) respond fast and regulate minute to minute arterial BP. * SLOW --- Renin angiotensin and Aldosterone respond slow. * Baro receptor mechanism present in carotid sinus located near bifurcation of common carotid artery respond to high or low BP. Additional baro receptor present in Aortic arch which respond only to in arterial P. (but not to BP) * Baro receptor the firing rate of carotid sinus nerve IX (glossopharyngeal) which carries information to vasomotor center in brain. * Set point for the mean arterial P in vasomotor center is 100 mmHg so if set point , vasomotor center reduce it by parasym vagal out flow to heart and sympathetic out flow to the heart and blood vessels ( vasoconstriction). * Renal perfusion P Renin release Renin catalyze angiotensinogen to angiotensin I (in plasma) than angiotensin I is converted to AT II (in lung) by ACE. * AT II vasoconstriction of arterioles (TPR) & stimulates Aldosterone secretion. (K+ & blood vol also stimulate Aldosterone secretion )
* Aldosterone Reabsorption of salt and water by distal tubules blood Vol and mean arterial P. OTHER REGULATION OF ARTERIAL BLOOD PRESSURE : 1. Cerebral Ischemia -- both parasympathetic & sympathetic outflow. (that is why is very hard to control BP in CVA or strokes) Mean arterial P to life threatening level. Flow to other organ (eg kidney) significantly reduced Renin, AT II TPR. * Cushing reaction -- in IC Pressure compression of cerebral blood vessel cerebral ischemia sympathetic out flow contractility, TPR with simultaneous reduction in Heart rate (Parasym). 2. Chemoreceptor in aortic and carotid bodies are very sensitive to hypoxia (because of very high rate of O2 consumption) stimulate vasomotor center to restore BP.
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3. Vasopressin (ADH) release in response to blood Vol or P. ADH act on --- V1 receptors cause vasoconstriction ( TPR) V2 receptors reabsorption of water by distal tubule and collecting duct. 4. Atrial natriuretic Paptide (ANP) release in response to atrial P dilation of arterioles (inhibit vasoconstriction), & TPR. It also salt & water excretion and inhibit Renin release. ------------------------------------------------------------------* Flow through capillaries is regulated by contraction and relaxation of the arterioles and the precapillaries sphincters. Remember capillaries do not have smooth muscles instead containing endothelial cells. * BBB is a tight cleft b/w endothelial cells of capillaries. In intestine & liver these cell clefts are wide open called Sinosoids it allow protein to cross. ( 3 types of subs cross capillary wall 1. lipid soluble subs. 2. small water soluble subs. 3. large water soluble subs via pinocytosis. )
FLUID EXCHANGE ACROSS CAPILLARIES : * It can be determined by Starling equation Jv = K [ ( Pc - Pi ) - ( c - i ) ] Jv is fluid flow and Kf is filtration coefficient Pc (Capillaries hydrostatic P) when it cause net filtration. Pc is higher at arteriolar end of the capillaries than venous end. Except in glomerular capillaries where it is nearly constant. ( Remember arteriolar or venous P Pc but venous P has greater effect on Pc )
Pi (Interstitial fluid hydrostatic P) Normal Pi is 0mmHg . in Pi oppose filtration out of the capillaries. c (Capillaries oncotic or colloid osmotic P) when opposes filtration out of capillaries. i ( Interstitial oncotic or colloid osmotic P) when favor filtration out of capillaries. Factor that increase filtration are Pc, Pi. c, i . -------------------------------------------------------------------FUNCTION OF LYMPHNODE: * Excess filtered fluid is returned to circulation via lymph. One way flap valve permit unidirectional lymph flow. Skeletal muscle contraction also aid it. * Edema caused by excess filtration or blocked lymphatics or by Pc, c, K. (K due to burn & inflammation) * EDRF (produce by endothelial cell) relaxes smooth muscle by Guanylate cyclase mech produce GMP. ( one form of EDRF is Nitricoxide )
* Ach vasodialation by stimulation of EDRF production. ------------------------------------------------------------------SPECIAL CIRCULATION :Blood flow is regulated by altering arteriolar resistance, can be varied depends upon metabolic need. Autocirculation -- When perfusion P arteriolar smooth muscle stretches follow by contraction vasoconstriction occur (by this maintain constant flow)
Active Hyperemia -- Is blood flow to organ proportional to its metabolic need. eg . Heart Reactive Hyperemia -- Is in blood flow to an organ after a period of occlusion to flow. eg . Heart Vasodilator metabolites are CO2, H+, K+, lactate and Adenosine. ------------------------------------------------------------------VASOACTIVE HORMONES : * Histamine arteriolar dilation & venoconstriction. It Pc & cause local edema. (Wheal is an edema results from local histamine release).
* Bradykinine arteriolar dilation and venous constriction it also cause edema. * Serotinin arteriolar vasoconstriction. It release upon vessel damage and prevent blood loss. * Prostaglandins --- PGI 2 (prostacyclin) and PGE vasodilation PGF vasoconstriction TxA2 vasoconstriction CORONARY ARTERY CIRCULATION : 5% is resting cardiac output. * Control by local metabolites specially hypoxia and Adenosine vasodilatation to blood flow.
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* Exhibit Autoregulation, active and reactive hyperemia. * During systole mechanical compression of the coronary vessel reduces blood flow, Reactive hyperemia occurs after that brief period of occlusion to replay the O2 dept. (Mechanical Effect) * Sympathetic nerev play a minor role. CEREBRAL CIRCULATION : Is 15 % of resting cardiac out put. * Control by local metabolites specially CO2 ↑ or ↓ of pH vasodilatation of cerebral arteries to blood flow. * Vasoactive subs in general circulation have little or no effect on cerebral circulation because of BBB. SKELETAL MUSCLE CIRCULATION : Is 20 % of resting cardiac out put. * At rest symp control of blood flow predominate where as during exersize local metabolites control over rides sympathetic control. * Local metabolites like lactate, Adenosine, K+, dilates vessel and increase blood flow. * Mechanical effects compensate by reactive hyperemia. (due to temporary compression of arterioles with resultant vasodilatation )
* receptors cause vasoconstriction where as receptors cause vasodialation. SKIN CIRCULATION : Is 5 % of resting cardiac output. * Skin have extensive sympathetic innervation and flow of blood is in extrinsic control (temperature regulation). PULMONARY CIRCULATION : Is 100% of cardiac out put. Local metabolites are most imp mechanism. RENAL CIRCULATION : Is 25% of resting cardiac out put. ----------------------------------------------------------------* Upon Standing (gravity) in venous P, Pc Filtration initial in stroke vol & cardiac output compensatory mech starts (via carotid baro receptors) HR , TPR BP return to normal BP. * On Exercising HR , stroke vol , cardiac output , Arterial P (slightly), Pulse P (due to stroke vol), TPR (due to vasodilatation of skeletal m bed), Arterio venous O2 difference ( due to increase O2 consumption). * On Hemorrhage HR , TPR , contractility , unstressed vol (stress vol ), Renin , AT II , Aldosterone , EN & norEN , ADH . ( Remember vaso constriction occur in skeletal, splanchnic & cutaneous vascular bed; but it does not occur in coronary and cerebral vascular bed because to ensure maintained blood flow to heart and brain ). ----------------------------------------------------------------------------------
* Blip is aortic P tracing occur following closure of aortic valve also called dicrotic notch or Incisura. * Rapid flow of blood from atria to ventricle cause 3rd heart sound (normal in children but associated with dis in adults). * Inspiration split the second heart sound. * Ventricle filling is divided into Rapid ventricle filling & Reduced ventricle filling (Diastasis) which is last part of ventricle filling curve. NEUROPHYSIOLOGY * Autonomic nervous sys (symp, parasymp & enteric) is distinct from Somatic nervous sys which innervate skeletal muscles and use ACh as a NT where as receptor is nicotinic. * Symp neurotransmitter is norEN in effector organ except in sweat glands where it is ACh and receptors are muscarinic. * Parasym and Symp receptors in ganglion are Nicotinic and NT is ACh. * Symp ganglia are located in paravertebral chain where as parasymp ganglia are located in effector organ. * Preganglionic symp fiber are short and synapse in autonomic (paravertebral) ganglia its cell bodies are present in CNS & Postganglionic symp fibers are long & synapse in effector organ & its cell bodies are located in Autonomic (paravertebral) ganglia. * Preganglionic parasymp fibers are long and synapse in autonomic ganglion in effector organ it cell bodies are present in CNS & postganglionic parasym fibers are short & synapse on effector organ, its cell bodies are present in autonomic ganglion. * Parasymp receptor in effector organ is Muscarinic but in skeletal muscle (somatic) is Nicotinic. * Adrenal medulla is a special case in which preganglionic fiber synapse directly on chromaffin cells of adrenal medulla it use ACh as NT & secret EN 80% & norEN 20% . (because remember preganglionic fibers normally synapse on ganglion).
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ADRENERGIC RECEPTOR TYPES : 1. 1 - located on smooth muscle except bronchial smooth muscle Excitation (via IP3 mech) & is equally sensitive to EN & norEN. 2. 2 - located on smooth muscles, Presynaptic nerve terminal, platelets and fat cells Inhibition (via cAMP mach). 3. 1 - located in heart, kidney and fat cells Excitation (via cAMP mach). 4. 2 - located on vascular, bronchial and GI smooth muscles Relaxation (via cAMP mach) and is more sensitive to EN than norEN and more sensitive to EN than receptors. * When small amount of EN release from adrenal medulla cause vasodilation but when large amount of EN release from adrenal medulla for eg as in pheochromocytoma results into vasoconstriction (via receptors).
* 1 --- constrict pupil. where as 1 --- heart contraction, renin secretion, and lipolysis in fat cells. * In sweat gland sympathetic action sweating but neurotransmitter is ACh and receptors are muscarinic. CHOLINERGIC RECEPTOR TYPE : 1. Nicotnic receptors (activated by ACh or Nicotine) are located in autonomic ganglia & neuromuscular junction Excitation ( nicotinic or Ach receptors are ion channel for Na+ and K+ ). Ganglion blockers ( Hexamethonium, Trimethpphan ) block nicotinic receptor for Ach in autonomic ganglia but not at neuromuscular junction (because receptors are not identical). 2. Muscuranic receptors located on * In Heart M2 receptors are located on SA node Inhibition (via cAMP) by the rate of spontaneous depolarization. * In Glands Exitation (via IP3) * In Smooth muscle Excitation (via IP3) with resultant constriction of bronchial smooth muscle, contract bladder wall & relax sphincter, GI motility and relax sphincter. (note: in vascular smooth muscle M receptors cause relaxation or vasodilation) --------------------------------------------------------------------------------------SENSORY SYSTEM : A. Type of sensory transducer : 1. Mechano Receptors -- * Pacinian Corpuscles (encode vibration and tapping) & adopt rapidly * Meissners corpuscles present on non hairy skin (encode velocity) & adopt rapidly * Merkels disc ( location ) & adopt slowly * Ruffini,s corpuscles (encode pressure) & adopt slowly * Joints, stretch receptors in muscles * Hair cell in auditory and vestibular system.
2. Photo Receptors ------------- Rods and Cones of the retina. 3. Chemo Receptors ----------- Olfactory Receptors, taste receptors, osmo receptors and Carotid body Receptors. 4. Temp & Pain Receptors ---- Noci Receptors. (Pacinian vibrates meissners run (velocity) to merkel location and shares ruffini's pressure)
B. Fiber type and velocity : --------------------------------------------------------------------------------------------------------------------------------------------------------------------------General Fiber Type
Sensory Fiber Type
Diameter
Conduction Velocity
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------A - Alpha (large motoneuron) Extrafusal fiber
I a (muscle spindle afferent) I b (golgi tendon organ) A - Beta ( Touch & Pressure) II Sec Afferent of muscle spindle touch & pressure A - Gamma ( motoneuron to muscle spindle) Intrafusal fiber A - Delta (touch, pressure, temp, pain) III Touch, Pressure, Temp & Fast Pain B Preganglionic Autonomic Fiber C Slow Pain, Postganglionic Autonomic Fiber IV Pain, Temp (unmyelinated)
Largest Largest Medium Medium Small Small Smallest
Fastest Fastest Medium Medium Medium Medium Slowest
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------* Receptive Field in the region that contain sensory transducer can be excitatory or inhibitory. STEP IN SENSORY TRANSDUCTION : Stimulus arrives in sensory receptors opening of ion channel in sensory receptor inward current cause depolarization ( except in photo receptors where light cause hyper polarization). * Action potential is fired only when stimulus to receptor potential is large enough to exceed threshold. ADOPTATION OF SENSORY RECEPTOR : 1. Slow adopting receptor eg. muscle spindle, pressure, slow pain. Respond relatively to prolong stimulus. 2. Rapidly adopting receptor eg. pacinian corpuscles, light touch respond fast but show decline in action potential frequency with time in response to constant stimulus.
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SENSORY PATHWAY : a. 1st order neuron --- Primary afferent neuron receive signals. These cell bodies are located in dorsal root ganglia and CN ganglia. b. 2nd order neuron --- Located in spinal cord & brain stem. Receive information from primary afferent neuron & send it to thalamus. c. 3rd order neuron --- Located in sensory nucleus of thalamus from here it send information to cerebral cortex. d. 4th order neuron --- Located in cortex and result in conscious perception of stimulus. -------------------------------------------------------------------------------------------PATHWAY OF SOMATOSENSORY SYSTEM : 1. Dorsal Column System: * Consist of group II fiber which run in the Dorsal Root; it ascend ipsilaterally to the Nuc Gracilis & Cuneatus of (Posterior column sys)
medulla from here 2nd order neuron cross the mid line and ascend to the contralateral thalamus. * Dorsal column system process sensation of touch, pressure, vibration, and movement.
2. Anterolateral System: * Consist of group III and IV fibers which enter the spinal cord and terminate in the dorsal horn. Form here 2nd order neuron sensory project across the midline to the Anterolateral quadrant & ascend to the contra lateral thalamus.
*
Anterolateral system process sensation of temp and pain.
* Destruction of thalamic nuclei result in loss of sensation on the contra lateral side of the body. SOMATOSENSORY CORTEX :- * Major somatosensory area of cortex is S I and S II. S I have somatotropic representation similar to thalamus. This map of body is called Homunculus (HAL). PAIN: * Perceive by Noci receptors which are free nerve ending and neurotransmitter is Substance P (opiate inhibit it). * Fast pain fibers are group III fibers shows rapid onset and offset and is localized. * Slow pain fibers are C, (IV) fibers perceive aching, burnig, throbbing sensation and is poorly localized. -----------------------------------------------------------------------------------------VISION : * Refractory power of lens is measured by Diopters. 10 Diopters = 10 cm * Emmetropia -- Normal -- light focus on retina. * Hyperopia -- Farsightedness -- Light focus behind the retina (convex lens). * Myopia -- Nearsightedness -- Light focus in front of retina (Biconcave lens). * Astigmatism -- Curvature of lens is not uniform (cylindrical lens). * Presbyopia -- Loss of accomodation of lens with aging. The near point appear more farther from eye (convex lens). * Receptor cells are Rod and Cones which are not present at Optic disc and create a blind spot. * Few cones synapse on single Bipolar Cell which further synapse on single Ganglion Cell this arrangement cause high acuity & low sensitivity. * Many Rods synapse on single bipolar cell which results into less acuity & greater sensitivity . (because many rods can activate single bipolar cell).
* In FOVEA where acuity is high Cone Bipolar ratio is 1:1 . * Horizontal and Amacrine Cell form local circuit with Bipolar Cell. * Axon of the Ganglion form Optic Nerve & Optic Tract terminate in the Lateral Geniculate Body of the thalamus. * Fiber from Lateral Geniculate Body form Geniculocalcarine Tract and pass to cortex of Occipital lobe. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------FUNCTION RODS CONES ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Sensitivity to light Sensitive to low intensity to light ( Night vision ) Sensitive to high intensity light ( Day vision ) Acuity Low visual acuity ( not present in FOVEA ) High visual Acuity ( Present in FOVEA ) Dark Adaptation Rod adopt later Cones adopt first Color vision NO NO More at peripheral of retina YES YES
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------* Cutting the Optic nerve Blindness of ipsilateral eye. * Cutting the Optic chiasm Hetronymous Bitemporal Hemianopsia. * Cutting the Optic Tract Homonymous Contralateral Hemianopsia. * Cutting the Geniculocalcarine Tract Homonymous Hemianopsia with Macular sparing. * Cutting unilateral temporal lobe radiation Homonymous Quadrantopia (pie in the sky) * Bilateral visual cortex lesion Macular sparing.
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Photo Reception of Rods: * In Rod Photosensitive element is Rhodopsin composed of Scotopsin & Retinine ( Aldehyde of vit A ) . Vit A deficiency cause night blindness. (because Vit A is essential for regeneration of Rhodopsin). * Light on retina convert 11-cis Rodopsin All transRodopsin MetaRodopsin II (active form) than Metarodopsin II activates G protein called Transducin which in turn activate Phosphodiesterase Phosphodiestrase further catalyze conversion of cGMP into 5‘ GMP (c GMP level ) . Than cGMP results into closure of Na+ channel & Hyperpolarization of the cell Membrane . ( light cause degree of hyperpolarization ).
* Excitatory NT hyperpolarize bipolar & horizontal cell in response to light. Inhibitory NT depolarize it in response to light.
vs.
Receptive visual Field : * Light hit the centre of receptive field & depolarize (excite) the Ganglion cells & constitute On Center Off Surround receptive visual field pattern. (On Center Off surround is another possible pattern in which light hits the surround of receptive field & hyperpolarize (inhibit) the ganglion cell) * Lat Geniculate Cell of the Thalamus retained the Center - Surround ON - OFF pattern transmitted from Ganglion cell. RECEPTIVE FIELD OF VISUAL CORTEX : Detects shape and orientation of figure. Visual Cortex comprise of three Layers. 1. Simple Cells (have center -surround On - Off pattern & are elongated Rods) --- Respond to Bars of light with correct position & Orientation. 2. Complex Cells --- Respond best to moving Bars and edge of light. 3. Hyper Complex Cells --- Respond best to lines with Particular Length and to curve and angles. -------------------------------------------------------------------------------------------------------------------AUDITON : * Frequency measure in Hertz where as Intensity in Decibles. Fig:
* Middle ear is air filled where as inner ear is fluid filled. * Middle ear contain Tympanic mem, Ossicles (malleus, incus, stapes) and Oval window where as Inner ear consist of Bony labyrinth (semicircular canal, cochlea, vestibule) and series of Ducts called Membranous labyrinth which contain endolymph (inside the duct) and perilymph (out side the duct).
* Sound cause Tympanic mem to vibrate, in turn Ossicle vibrate and pushes the stapes in to the Oval Window ( a mem b/w inner ear and middle ear ) which displaces the fluid in the inner ear. * Sound energy is amplified by lever action of Ossicles and send conc of sound wave from Tympanic mem to Oval Window. COCHLEA consist of three Tubular canals. 1. Scala Vestibuli --- Contain perilymph and is in Na+. 2. Scala Tympani --- Contain Perilymph and is in Na+. 3. Scala Media --- Contain endolymph and is in K+*
( Scala Media is Bordered by Basilar Mem the site of Organ of Corti ).
Fig:
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ORGAN OF CORTI is located on Basilar mem. Its Receptors are inner Hair cells (in single row) & outer Hair cells (in parallel row) Outer Hair cells are greater in number than inner Hair cells. * Cilia protrudes from Hair cells and imbedded into Tectorial mem . * Spiral Ganglion contain cell bodies of CN VIII which synapse on Hair cells. * Sound wave vibrates Organ of Corti Basilar mem to vibrate & push against Tectorial mem Hair cells to bend bending of cilia (which cause change in K+ conductance) Depolarization Ossillating potential results. (bending in other direction cause hyperpolarization)
* Ossillating Potential (Cochlear microphonic potential) of Hair cell intermittent firing of Choclear nerve. ENCODING OF SOUND WAVE : * Base of the Basilar mem ( near Oval and Round window ) is narrow and stiff it respond best to high Frequency. * Apex of the Basilar mem ( near Helicotrema ) is wide and compliant it respond best to low Frequency. CENTRAL AUDITORY PATHWAY : * Cochlear nerve Fiber ascend through Lateral Laminiscus Inferior Colliculus Middle Geniculate nucleus of thalamus auditory Cortex.
* Fiber may crossed or uncrossed that’s why lesion of the chochlea of one ear cause unilateral deafness where as more central unilateral lesion does not cause complete unilateral deafness. * Ability to recognize a patterned sequence is a property of Cerebral Cortex. * Remember always Medial geniculate to Ear and lateral geniculate to Eye. VESTIBULAR SYSTEM : * Vestibular organ is a membranous labyrinth consisting of three perpandicular canal filled with Endolymph. 1. Semicircular canal --- Detect angular acceleration and rotation. 2. Utricle --- Detect linear acceleration. 3. Saccule --- Also detect Linear acceleration . * The vestibular receptor cells are Hair cells located at the end of each semicircular canal. * Vestibular Hair cells are embedded in gelatinous substance called Capula. * Kinocilium is a single long cilium where as Stereocilia are small cilium. * If Sterocilium bends toward the Kinocilium Hair cells Depolarize where as If Sterocilium bends away from Kinocilium Hair cells Hyperpolarize.
* During initial counterclockwise rotation Left Horizontal canal is excited & Right Horizontal canal is inhibited but after few seconds endolymph catches up the movement of head & capula; cilia return to their upright position.(no more hyperpolarization or depolarization)
* When head suddenly stops endolymph continues to move to counterclockwise for a while (cause cilia to move in opp direction) if the hair cell was depolarized with initial movement, it will now hyperpolarized and hyperpolarized one will depolarize. * Vestibular - Occular Reflex : Nystagmus --- An initial rotation of head cause eye to move slowly in opposite direction when limit of eye movement reaches the eye rapidly snap back than move slowly again. (nystagmus in rest arise from disruption in central or peripheral vesticular connection)
Post rotatory nystagmus --- Occur in the opposite direction of head Rotation. ----------------------------------------------------------------------------OLFACTORY receptor cells are present on epithelia and are true neurons. It conduct action potential to CNS via CN I. * These neuron are the only eg. in nervous system that turn over and replace neuron. * CN I carries information from receptor cell to Olfactory bulb, the Axon of olfactory nerve is unmyelinated C fiber and are smallest therefore slowest. * Olfactory epithelium is also innervated by trigeminal nerve V which detect Noxious stimulus such as Amonia. * Olfactory nerve passes through the Cribriform plate to Olfactory bulb, its fracture Hypoosmia, Anosmia.( CN V response is intact )
* Mitral cells in the Olfactory bulb are 2nd order neurons from Olfactory Tract and project to Prepiriform Cortex. * Odorant molecules bind to the olfactory receptor neuron activate G protein activates adenylate cyclase cAMP Open Na+ channel depolarization of receptor potential Fire action potential.
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TASTE : * Taste buds are located on special Papillae & are covered with micro villi. ( taste receptors are present on taste bud ) * Ant 2/3 of tongue has Fungiform Papillae detect salty and sweety sensation and is innervated by Facial nerve VII. * Post 1/3 has Circum vallate & Folliate papillae detect sour & bitter sensation & is innervated by Glossopharyngeal nerve IX. * Back of throat and Epiglottis is innervated by vagus nerve X. * CN VII, IX, X enter the medulla ascend in solitary tract where 2nd order neuron terminates in solitary nucleus; from here itproject primarily ipsilaterally to ventral posteromedial nuc of thalamus taste cortex (which is present in the ventral region of Post central gyrus).
-------------------------------------------------------------------------MOTOR SYSTEM :* Motor unit is a single motoneuron plus muscle fiber that it innervates. (single motoneuron may innervate few muscle for fine movement & many muscle for large movement) .
* Motoneuron pool is a group of neuron that innervates fibers with in same muscle. * Force muscle contraction is graded by recruitment of additional motor unit (size principle). * Small motoneuron -- innervate few muscle fibers, has lower threshold therefore fire first and generate small force. * Large motoneuron -- innervate many muscle fibers, has highest threshold and therefore fire last and generate large force. ------------------------------------------------------------------------MUSCLE SENSORS :- 4 Types of muscle sensors 1. Muscle spindle a has parallel arrangement with extrafusal muscle fiber, detect both static & dynamic changes in muscle length. 2. Golgi tendon organ b has serial arrangement with extrafusal muscle fiber detect muscle tension. 3. Pacinian Corpuscles detect vibration. 4. Free nerve ending , V detect noxious stimuli. TYPE OF MUSCLE FIBER :1. Extrafusal fiber -- make muscle bulk and stimulate by motoneuron. It provide force of muscle contraction. 2. Intrafusal fiber -- are smaller than extrafusal fiber. It encapsulated to form muscle spindle & run parallel to extrafusal fiber but do not run entire muscle length. Intrafusal Fiber a type afferent muscle strength (dynamic changes) Nuc bag fiber Nuc chain fiber muscle change (static change) type afferent
------------------------------------------------------------------------* Muscle spindle -- Finer movement need greater no of muscle spindle in muscle. (muscle spindle consist of intra & extra fusal muscle fiber)
* There are two type of intrafusal fiber present in muscle spindle. 1. Nuclear Bag fiber: Detect Dynamic changes (rate & change in muscle strength at motion) & is Innervated by a afferent. 2. Nuclear Chain fiber: Detect Static change (at rest) in the muscle length & is innervated by group afferent. FUNCTION OF MUSCLE SPINDLE : Muscle spindle opposes over stretching of muscle by contracting it. * Stretched muscle further stretches Muscle spindle Stimulate a (velocity) & group (static) afferent fibers stimulate motoneuron in spinalcord contraction. Function of Motoneuron :- Motoneuron Innervate intrafusal muscle fiber it adjust the sensitivity of muscle spindle. & motoneuron are coactivated so muscle spindle remain sensitive to change in muscle length during contraction. MUSCLE REFLEXES --------------------------------------------------------------------------------------------------------------------------------------------------------------------------REFLEX NO OF SYNAPSE STIMULUS AFFERENT FIBER RESPONSE ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Stretch Reflex ( Knee Jerk ) Monosynsptic Stretch Muscles a Muscle contraction Golgi Tendon Reflex ( Clasp Knife ) Disynaptic Contract muscle b Muscle Relaxation Flexion withdrawal Reflex Polysynaptic Pain , , V Ipsilateral Flexion & contralateral ( after touching Hot object ) Extension ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
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Stretch Reflex -- a afferent synapse on motoneuron to cause contraction in the muscle that was stretched. ( motor activity the sensitivity of muscle spindle which result into exaggerated stretch reflex ).
Golgi tendon Reflex -- Activated muscle contraction stimulate b afferent fiber of Golgi tendon than b inhibit interneuron in spinal cord which further inhibit motoneuron Relaxation of muscle that was originally contracted. Clasp Knife reflex is an exaggerated form of the Golgi tendon ref it can occur in Corticospinal tract dis → ( spasticity ). Flexion withdrawal reflex -- After touching a hot object pain stimulus from , , and V afferent fiber cause ipsilateral Flexion and contralateral extension ( cross extension reflex ) to maintain balance. After discharge does not allow the muscle to relax for some time because of persistent neuronal activity in polysynaptic circuit. --------------------------------------------------------------SPINAL ORGANIZATION OF MOTOR SYSTEM : 1. Convergence is when more than one muscle spindle stimulates single motoneuron ( a afferent ) produce spatial Summation ( more than one input bring muscle to threshold ) & temporal summation ( input arrive rapid succession ). 2. Divergence is when a afferent (muscle spindle) project to more than one or all motoneuron of the homonymous mus. 3. Recurrent inhibition (Renshaw cells): Renshaw cells are inhibitory neuron it inhibit motoneuron (- ve feed back ) in ventral horn of spinalcord. It receives input from collateral axons of motoneuron. --------------------------------------------------------------BRAIN STEM CONTROL OF POSTURE : Motor center and Pathway are of two types, 1. Pyramidal Tract -- is Corticospinal & Corticobulbar Tract. Both Pass through medullary pyramids. 2. Extrapyramidal Tract -- are all other pathway. -------------------------------------------------EXTRAPYRAMIDAL TRACTS AND ITS ORIGINS : 1. Rubro spinal Tract -- Originate in red nuc & project interneuron to lateral spinalcord. It stimulate flexors & inhibit extensor. 2. Lateral Vestibulospinal Tract -- Originate in Dieter’s nuc & project to Ipsilateral motoneuron & interneuron. It stimulate extensors & inhibit flexors. 3. Pontine Reticulospinal Tract -- Originate in nuc in pons & project to Ventromedial spinalcord. It stimulate both extensors & flexors.(but more Ext) 4. Medullary reticulospinal Tract -- Originate in medullary Reticular formation & project to spinalcord. It inhibit both extensor & flexor.(but more ext) 5. Tactospinal Tract -- Originate in superior colliculus & project to cervical spinal cord. It control neck muscles.
EFFECT OF TRANSECTION OF SPINAL CORD : 1. Paraplegia (Loss of voluntary movement) below the level of lesion. 2. Loss of conscious sensation below the level of lesion. 3. Initial loss of reflexes (spinal shock) flaccidity occur below the level of lesion due to loss of & motoneuron. ( with time partial recovery and return of reflexes or even hyperreflexia will occur )
* C7 lesion results into loss of sympathetic tone to the heart HR & BP . * C3 lesion will stops breathing because respiratory muscle disconnected from brain stem Control center. * C1 lesion cause Sudden death eg. as in hanging. EFFECT OF TRANSECTION ABOVE THE SPINAL CORD : * Lesion above Lateral Vestibular Nucleus -- remove inhibition from higher center and cause excitation of and Motoneuron Decerebrate rigidity (rigid posture). * Lesion above Pontine Reticular formation -- removal of inhibition from pontine reticular formation & resultant excitation of & motoneuron & cause Decerebrate rigidity (rigid posture) * Lesion above the Red Nucleus results in Decorticate Posturing and intact tonic neck reflex. ----------------------------------------------------------------------CEREBELLUM :- Central control of movement. FUNCTIONS --- 1. Control of Balance an eye movement conduct by Vestibulo Cerebellum. 2. Planning and Iniciation of movement control by Ponto Cerebellum. 3. Synergy (Control of rate, Force, Range and Direction of movement) control by Spino Cerebellum.
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Layers of cerebellar cortex : 1. Granular Layer ( inner most ) -- contain granule cells, Golgi II cells & Glomeruli. ( In glomeruli axons of mossy fibers form synapse on granular & golgi II cells ). 2. Perkinji Cell Layer ( middle layer ) -- out put is always inhibitory. 3. Molecular Layer ( outer layer ) -- contain Stellate & Basket cells, Dendrites of perkinji & golgi type II cells & parallel fibers (axons of granule cells).
Connection of Cerebellar Cortex : * Input of cerebellar cortex : 1. Climbing Fibers - Play role in cerebral motor learning. It originate in inferior Olive (medulla) make multiple synapse on perkinji cells results in complex Spikes. 2. Mossy Fibers - Originate in brain stem & spinalcord. It synapse on perkinji fibers (via interneuron) & on glomerular Complex. Mossy fiber give rise to parallel fiber excite multiple perkinji cells as well as inhibitory neuron inhibition. Out put of cerebellar cortex : * The only out put from cerebellar cortex are perkinji cells and is always inhibitory (neurotransmitter is GABA) * Inhibitory out put project to deep cerebellar nuclei and vestibular nuclei. It regulates synergy. Disorder of Cerebellum ( Ataxia ) : Lack of coordination: (Poor execution & delayed inhibition of movement), Inability to perform rapid alternating movement called Dysdiadochokinesia.
Intension tremer occur during voluntary movement. Rebound Phenomenon - inability to stop movement. -----------------------------------------------------------------------BASAL GANGLIA :- Control of movement * Basal ganglia plan and execute smooth movement by modulating thalamic out flow to motor cortex. Many of its synaptic connection are inhibitory and use GABA. (Its lesion results into loss of GABA) Basal Ganglia consist of :1. Globus pallidus Lesion Inability to maintain postural support and athetosis (involuntary slow movement of hand & foot). 2. Sub Thalamic Nucleus Lesion Wild flinging movement called Hemiballismus. (caused by release of inhibition on contralateral side)
3. Straitum Lesion Quick continuous uncontrollable movement as in Huntington. (caused by release of inhibition) 4. Putamen Lesion involuntary purposeless muscular movement called Chorea. 5. Substantia Negra Lesion Destruction of Dopaminergic neuron Over reactivity of inhibitory pathway of Straitum & Globus pallidus Lead pipe rigidity, resting tremor & reduced voluntary movement (Parkinson Dis). MOTOR CORTEX :1. Premotor Cortex & Supplementary Motor Cortex ( area 6 ) generate a plan for movement . * It is active during Mental Rehearsal for movement which than transfer to primary motor cortex for execution. 2. Primary Motor Cortex ( area 4 ) is responsible for execution of movement. * Epileptic event in Primary motor cortex Jacksonian Siezures. * Homunculus is upside down Representation of the Human Body in cerebral cortex. --------------------------------------------------------------------------
HIGHER FUNCTION OF CEREBRAL CORTEX :1. EEG Findings : * EEG wave consist of alternating excitatory & inhibitory synaptic potential in the pyramidal cell of the cerebral cortex. * EEG change occur due to cortical evoked potential. In alert adult waves predominate & Upon relaxation waves predominate where as during sleep slow waves predominate.
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2. SLEEP : * Sleep wake cycle occur in circadian rhythm which resides in Suprachiasmatic nucleus of hypothalamus, which receives input from retina. * Rapid eye movement sleep occur every 90 min. During REM sleep EEG resembles that of awake person. Most dream occur during REM sleep. age and Benzodiazepine in REM sleep. * Slow wave sleep is Dream less Sleep ( dream do occur but cant be remmember ). 3. LANGUAGE :* Left hemisphere is usually dminant with respect to language even in left handed person. Its lesion Aphasia. * Right hemisphere is more dominant in Facial expression, Intonation (voice tone), Body language, and Spatial task. * Damage to Wernicks Area Sensory Aphasia ( difficult to understand written and spoken language ) . * Damage to Broca Area Motor Aphasia ( In which speech and writing are affected but understanding is intact ). 4. Short Term Memory: Involve synaptic changes. 5. Long Term Memory: Involve structural changes & is resistant. ( bilateral hippocampus lesion no more new long-term memories) ---------------------------------------------------------------------BBB AND CSF : * BBB consist of endothelial cells of cerebral capillaries and choroids plexus epithelium. * Lipid soluble subs like CO2, O2, & H2O cross BBB freely but other subs transport (in & out) by carrier in choroid plexus epithelium. * Protein and cholesterol are excluded from CSF because of large molecule size. * Composition of CSF is same as interstitial cerebral fluid of brain. FUNCTION : * BBB maintain constant enviornment of neuron in CNS and prevent scape of CSF and neurotransmitter. * Non Ionized ( lipid soluble ) drug absorb more easily than ionized ( non lipid soluble ). * Inflamation, Radiation, or tumor cell may destroy BBB. COMPOSITION OF CSF & BLOOD CONC : --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------CSF BLOOD CSF BLOOD CSF BLOOD --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Na+ K+ Mg++ ClCa++ Creatinin HCO3Glucose Osmolarity Cholesterol & protein. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
TEMP REGULATION : * Thyroid hormone metabolic rate heat production ( by stimulating Na+ - K+ ATPase ). * Cold Temp Activate sympathetic sys metabolic rate & heat production (via receptors activation on brown fat) * Shivering is most potent heat generating response by Post Hypothalamus ( via & moto neuron contractions ). HEAT LOSS : * Heat loss response is also control by Post Hypothalamus. * Temp sympathetic tone to the skin and blood vessels shunting the warm blood near the surface of the skin heat loss by radiation and convection. * Heat can also loss by evaporation via sweat glands activity which is under sympathetic muscuranic control. HYPOTHALAMUS SET- POINT FOR BODY TEMP : * Temp sensors on the skin and hypothalamus read the core temp and relay information to ant hypothalamus which compare core temp with SET - POINT temp. * If core temp is below or above normal it activate SET - POINT heat generating or losing mechanism via Post hypothalamus. * Cold and Pyogens ( inflammatory products and mediators ) the SET - POINT temp.
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FEVER : Pyogens produce IL-1 which act on ant hypothalamus to the production of prostaglandins which the SET – POINT temp and generate heat (fever). HEAT EXHAUSTION AND HEAT STORK : * Heat exhaustion: is caused by excessive sweating Blood vol BP Syncope . * Heat stork: occur when body temp to the point of tissue damage due to impaired sweating response core temp. * Hypothermia: results when temp is low and shivering & metabolism can not adequately maintain core temp near SET POINT. * Malignant hyperthermia: caused by inhalation anesthetics in susceptible individual. It is characterized by in O2 consumption and heat production by skeletal muscle rapid in body temp. ---------------------------------------------------------------------Few Points * Renshaw cells (neuron) respond to Ach and receptor is nicotinic. * Parasympathetics contract smooth muscle but relax sphincter by muscarinic receptors. * Sympathetics relax smooth muscle and contract sphincters by receptors. exception in eye where receptors contract radial muscle and cause mydriasis. * 1 -- In heart cause contraction where as in kidney cause Renin release. * 2 -- Relax smooth muscle * 3 -- In Adipose tissue lipolysis. * In carotid sinus Baro receptors respond strong to rising Pressure than falling pressure. * Protein produce by platelets is thromboplastin. * Cerebellar lesion cause intention tremor (tremor during voluntary movement). vs. Parkinson dis cause resting tremor. Imp difference * Difference b/w decerebrate and decortical rigidity and other signs ?
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