Integration of Volume RegulationSlide # 1

Primary factors regulating Renin:

Angiotensinogen Renin 1. Perfusion pressure to the kidney stimulates; inhibits 2. Sympathetic stimulation to kidney via Beta-1 receptor 3. Na+ delivery to the macula densa delivery stimulates; delivery inhibits

Angiotensin I (AI) (ACE)

Primary factors regulating aldosterone:

1. Plasma [angiotensin II] (AII) stimulates release RAAS 2. Plasma [K+] stimulates release

Angiotensin II (AII)

Primary factors regulating AVP:

1. Plasma osmolarity stimulates release Aldosterone (Na+ and water retention) 2. Blood volume/pressure inhibits release

SummaryEdemaSlide # 2
Primary causes of edema (High yield for exam)
Pc: FlowVasodilation; Venous pressureVenous
obstruction; heart failure; Blood volume (Na+ retention)Heart

failure

vascular oncotic pressure: Liver; Kidney Capillary permeability: Inflammatory response

(TNF-alpha; histamine; bradykinin) if: HypothyroidMyxedema Lymphedema: Filarial (W Bancrofti); bacterial

lymphangitis (streptococci); trauma; surgery; tumor

High YieldIonic EquilibriumSlide # 3

[Cl-]OHigh Prot [Na+]iLow Prot [Cl-]iLow [Ca2+]iLow* [K+]iHigh [Ca2+]OHigh Prot [Na+]OHigh

Prot -70 mV (Em) +

[K+]OLow

*-refers to cytosolic free calcium

High YieldIonic EquilibriumSlide # 4

5 fundamental principles
1. Membrane potential (Em): electrical charge (voltage) across
a cells membrane.

2. Electrochemical gradient: term describing the combination

of chemical and electrical gradients driving the diffusion of ions.

3. Equilibrium potential: membrane potential that balances

chemical and electrical force across the membrane. In other words, the membrane potential that results in no NET diffusion of an ion. (Nernst equation)

4. Conductance (g) or permeability: ease with which an ion

crosses the cell membrane. Determined by number of open channels that allow the ion to pass through the membrane.

5. Driving force (net force): Resting membrane potential minus

equilibrium potential.

Fast Sodium ChannelsSlide # 5

M-gate (activation) Na+

TTX; STX; Caine

Pharmacology Integration
Na+ Na+

Outside

2+ Ca
Depolarization opens M-gate

Inside

Positive membrane potential and time close h-gate

h-gate Ciguatoxin (CTX)/Batrachotoxin (BTX) (inactivation) Closed at Em Open Inactivated

Repolariztion Tetrodotoxin (TTX)/Saxitoxin (STX)/Caine drugs

Nerve DysfunctionSlide # 6
Toxins/drugs
3,4-DAP; 4-AP

Increased excitability

Ion disturbances Hyperkalemia ( gradient) Hypocalcemia (Na+ channels)

hypereflexia; spasms; muscle fasciculations; CTX/BTX tetany; tremors; Central demyelination paresthesia; convulsions
by MS Ion disturbances

Alpha motor neuron

Demyelination Guillain-Barr syndrome (GBS)

Skeletal muscle

Hypokalemia ( gradient)
Hypercalcemia (Na+ channels) Neuronal loss ALS Aging

Toxins/drugs TTX/STX Local anesthetics

Weakness; fatigue; ataxia; hyporeflexia; paralysis; sensory deficit

Decreased excitability/Lack of conduction

Neuromuscular Junction (NMJ)Slide # 7

Demyelination of GBS can block action potential Botulinum toxin (Botox) prevents release of ACh ACh AChE inhibitors (organophosphates) Depolarizing & nondepolarizing blockers Lambert-Eaton syndrome: autoimmune

TTX
STX 3,4DAP 4-AP

Hyperkalemia/ hypocalcemia Hypokalemia/ hypercalcemia Voltage-gated Ca2+ channel

Ca2+

Latrotoxin

Na+

Myasthenia Gravis: autoimmune/congenital

Na+ K+
Nicotinic receptor

Voltagegated Na+

High Yield EKG ChangesSlide # 8

Hyperkalemia: Rate repol Sharp, spiked T wave
QT interval Hypokalemia: Rate repol U waves QT interval Transmural infarction

Path/Pharm Integration
Prinzmetal angina
ST Elevation Hypercalcemia QT interval

Hypocalcemia
QT interval ST Depression Subendocardial ischemia Classic (stable) angina

Muscle DysfunctionSlide # 9
Malignant hyperthermia (treat with dantrolene) Tetanus toxin (glycine in spinal cord) Exercise-induced McArdle

Spasms/ contractures

NM block TTX/STX Local anesthetics Botox ALS GBS

Flaccid
Alpha motor neuron Skeletal muscle

paralysis

Muscular dystrophies

Decreased force (weak)

McArdle

Severed nerve
Exercise-induced

Disuse Atrophy
Aging Protein wasting Pompe

High Yield RelationshipsSlide # 10

Q=
DP R
L R 4 r

DP R
Flow =

MAP = CO X TPR CO = HR X SV T Pr (LaPlace)

DV C= DP
PP = SV C

Uptake of O2 A V O2 difference

Reynolds number = (velocity) (diameter) (density) / viscosity MAP = 1/3 PP + diastolic pressure Pulse pressure (PP) = systolic - diastolic Uptake of O2 = Flow X A V O2 difference Cardiac Index = CO/ body surface area (BSA) EF = SV/EDV X 100 Velocity = Q/CSA P = height X density X gravity

Free Flow (Q)Slide # 11

Upstream Pressure
P = 80
Change R here

Downstream Pressure
P = 70

Q
Vasoconstrict

DP R

Deeeeep Thoughts
Vasoconstrictors
Sym (NE)alpha!!! Epialpha AII & AVP Alpha agonists NE releasers Reuptake blockers

Slide # 12

Brain
Arterioles are resistors!!
Total resistance (TPR/SVR) is sum of each resistor. Total resistance (TPR/SVR) is AFTERLOAD for heart. Think of each resistor as a faucet. Cant have all faucets open simultaneously.

Vasodilators

sym!!!
EpiBeta-2 metabolism & NO Alpha blockers NO releasers CCB K+ channel

Must have an adequate MAP to drive flow!!!!

= resistor

P=QXR MAP = CO X TPR

ComplianceSlide # 13

DV C= DP
Water

DV DP = C
Water

DV = DP X C

High Compliance

Low Compliance

Venous ReturnSlide # 14
Venous Return is the flow of blood TO the heart.
Central blood volume is directly related to venous return. CVP and pulmonary wedge pressure are clinical markers of central blood volume Central blood Venous return is volume DIRECTLY related to (PRELOAD) blood volume and INVERSELY related to venous Pharm Integration: compliance Nitrates preferentially dilate veins ( their compliance) Venous Blood volume in? return Sympathetic stimulation compliance, thus venous return What does an elevated CVP suggest? blood volume; Venoconstriction Pump failure

Whole Body CV RegulationSlide # 15

MAP = CO X TPR
4 factors determine 1. HR ( CO exercise; CO with tachyarrhythmias) 2. Contractility (direct) 3. Afterload (inverse) Tone of arterioles Sympathetic (alpha) AII AVP Epi (alpha/beta-2) Metabolism NO Directly related to venous return Blood volume (direct) Venous compliance (inverse) Pharm integration

4. Preload (direct)

Effect of GravityCompensationsSlide # 16
Sympathetic activation:
Venous Pooling Constricts arterioles (TPRRec?)

HR/Inotropy (Rec?)
Constricts veins (Rec?)

ventricular volume (sensed by cardiopulmonary baroreceptors)

Arterial baroreceptors if MAP falls

Path/Pharm Integration
Orthostatic intolerance

vascular volume Venodilators; alpha blockers

Reflex sympathetic nervous system

Denervated heart/ heart failure

Dysautonomias (diabetes mellitus)

Short/Long Term MAP RegSlide # 17

Heart rate M2

Contractility b1 b1 Autonomic drugs Stroke volume F-S Cardiac output Shock

TPR a

Venoconstriction a VR Preload

VR
Blood volume Urine volume

Mean Arterial Pressure

Anti-hypertensive drugs Baroreceptor activity

Renin b A II

Stimulates

Parasympathetic activity Inhibits

Sympathetic activity

Aldo

High Yield Application of Fick Principle

For any given O2 consumption, a in delivery results in: 1) possible hypoxic/ischemic damage, & 2) a the amount of O2 in the veins draining the tissue.

Slide # 18
Fick Cell consumes VO2 = Q X (CaO2 CvO2) O2
O2 consumption O2 extraction (by the tissue)

Cao2

Cvo2

O2 delivery = Q X CaO2 Q Extraction Venous O2 CaO2 with same Q & extraction Venous O2

Valvular ProblemsSlide # 19
Stenosis: Narrowed opening through valve. Bottom line is increased resistance to outflow. Murmur when open Insufficiency (also called regurgitant and/or incompetent): Valve fails to close properly. Bottom line is backflow of blood occurs. Murmur when closed
Tip 1: Think of when valve is open and closed
Systolic murmur: Mitral/Tricuspid insufficiency; Aortic/Pulmonic stenosis Diastolic murmur: Mitral/Tricuspic stenosis; Aortic/Pulmonic insufficiency

Tip 2: Pressure/volume behind the defective valve

Forces Acting on the Respiratory SystemSlide #20

Key forces to be aware of to understand ventilation
Lung recoil: Force exerted by the alveoli; This is an INWARD force and is inversely related to compliance.

Chest wall recoil: Force exerted by the chest wall; At rest, this is an OUTWARD force.

Intrapleural pressure (IPP): Fluid pressure in the intrapleural space. It is the OUTSIDE pressure for the alveoli, airways, and blood vessels within the chest. Transmural (PTM) pressure gradient: Pressure gradient across alveoli and small airways (see handout, slide #21)

Transmural Pressure GradientSlide # 21

Transmural pressure (PTM) gradient is the pressure gradient across the wall of any tube or sphere.

Po

Pi

Alveolus, airway, or blood vessel

PTM = Pi - Po

IPPPulmonary Blood FlowSlide # 22

Increased output delays closing of pulmonic valve (physiologic splitting of S2)

Inspiration

MAP = CO X TPR

RA in chest expands pressure so Q (VR)

Increases pulmonary vascular resistance Flow to LH Becomes more negative PTM for pulmonary vessels; their volume increases

PTM = 0 -5 = 5

Veins here are unaffected Inspiration decreases vagal outflow to the heart, thus HR increases (respiratory sinus arrhythmia)

Pg 147

Severe VA/Q MismatchSlide # 23

FIO2 is helpful since there is SOME ventilation in the low VA/Q units

Flow from low VA/Q units (<<1)

Diagnostic signs: 1. Increased A a gradient 2. Increasing FIO2 helpful

Increased A a gradient

PAO2 = (Patm 47) FIO2 (PACO2/R)

Differential for Causes of HypoxemiaSlide # 24

Low PaO2 (hypoxemia)
A a gradient Normal

PAO2: calculate using alveolar air equation or use end-tidal PO2

Elevated

Cause is PAO2 Corrects PaO2 FIO2 corrects PaCO2 likely elevated Diffusion impairment

Increase FIO2 Doesnt correct PaO2

VA/Q mismatch

Cause is rightto-left shunts

HypoxemiaSlide # 25
PAO2: Obstructive disease; Drug overdose; Anesthesia; Altitude; Chest restriction, e.g., kyphoscoliosis

Diffusion Impairment: Restrictive disease (pulmonary fibrosis); Pulmonary edema (ARDS, Left ventricular failure)

VA/Q mismatch: Severe obstruction (Status asthmaticus, Cystic fibrosis, anaphylaxis); Infection (pneumonia); Partial occlusion from mucus plugs

Shunts: Atelectasis (pneumothorax; ARDS); complete occlusion of an airway (mucus plug, foreign object); TOF

Relationships/Equations for RenalSlide # 26

FF = GFR RPF Transport = excretion filtered load Filtered load = GFR X PX

FF impacts Pc!!!

Rate of excretion = UX X V

UPAH X V Renal UX X V clearance = PX CPAH = ERPF = PPAH

Renal blood flow =

ERPF 1- Hct

Factors Affecting GFR and FFSlide # 27

Glomerular cap pressure

Constrict efferent Dilate efferent Constrict afferent Dilate afferent

Peritubular cap pressure

Nephron plasma flow

GFR

FF

Uric AcidSlide # 28
Biochemistry Integration
Uric Acid H+ + Urate-

Gout UA Probenecid + UrateAt low tubular pH

Precipitate

Pharmacology Integration

UrateUrate-

Allopurinol

Xanthine Oxidase

Xanthine

Adenosine Guanosine

80-90% of Hypoxanthine urate is reabsorbed Guanine in PT

Lesch-Nyhan
Salvage

Elevated Anion GapMUDPILESSlide # 29

M: Methanol U: Uremia (renal failure) D: Diabetic ketoacidosis P: Paraldehyde I: Iron; Isoniazid L: Lactic acidosis E: Ethylene glycol; Ethanol ketoacidosis S: Salicylates; starvation ketoacidosis; sepsis

Normal Anion GapHARD UPSlide # 30

H: Hyperchloremia (Parental nutrition) A: Acetazolamide R: Renal tubular acidosis D: Diarrhea U: Ureteral diversion (ureterosigmoidostomy)

P: Pancreatic drainage (pancreatic fistula)

Acid-Base Decision TreeSlide # 31 Osis? ACIDOSIS ALKALOSIS (pH)

Low (Acidosis) Cause of the osis? Look at bicarb

High (Alkalosis) Cause of the osis? Look at bicarb Elevated Metabolic

Low Metabolic

Elevated

Low

Respiratory Respiratory

Compensation? Use Winters to determine what Paco2 should be

Compensation? Paco2 0.7 torr for every 1 mEq/L in bicarb

Determine if Determine if acute (1:0.1) or acute (1:0.2) or chronic (1:0.4) chronic (1:0.4)

NOTE: Paco2 in resp acidosis; compensatory metab alkalosis (compute Paco2) NOTE: Paco2 in resp alkalosis; compensatory metab acidosis (compute Paco2) NOTE: Calculate anion gap: [Na+ - (Cl- + bicarb)]

Properties of ReceptorsSlide # 32
E + S (ES) E + P Michaelis-Menten H + R (HR) response stimulus response

100 Velocity (% of max)

% Response Vmax: determined by [E] & [S]

100
[R] is one factor

50
[S] is limiting Km 0

50
[H] is limiting

[S]

[H]

Properties of ReceptorsSlide # 33
H + R (HR) response stimulus response 100 100 % Response A + R (AR) response stimulus response

% Response

[R] is one factor 50 [H] is limiting

50 [H] is limiting
EC50

[H]

Log [A]

Overview of AVP PathophysiologySlide # 34

High Plasma osmolality
Note: AVP=ADH

Low

Plasma AVP

Plasma AVP

High
(1O)

Low
*Nephro DI

High

Low

Dehydration (2O)
UOSM POSM

Neuro DI* (1O)

UOSM POSM

SIADH (1O)
UOSM POSM

Primary Polydipsia (2O)

UOSM POSM

>1

<1

>1

<1

MetabolismCortisolSlide # 35
Cortisol Gly synthase Gly FA phos Glucokinase FA Glucose Glucose synthase 6-P PFK-1 (via G6-phos PFK-2) Malonyl CoA Fructose 1,6AA Pyruvate bisphosphatase (alanine) kinase Acetyl CoA PEPCK PDH carboxylase OAA (thiamine) Pyruvate Acetyl CoA Pyruvate carboxylase Cortisol LDH (biotin) TCA Ketones Lactate
Glycogen

InsulinGlucagonSlide # 36
Glycogen

Insulin stimulates

Gly Glucagon stimulates synthase Gly FA phos Glucokinase FA Glucose Glucose Urea synthase 6-P PFK-1 (via G6-phos PFK-2) Malonyl CoA Fructose 1,6AA Pyruvate bisphosphatase (alanine) kinase Acetyl CoA PEPCK PDH carboxylase OAA (thiamine) Pyruvate Acetyl CoA Pyruvate carboxylase (biotin) TCA Ketones

Diabetes MellitusSlide # 37
Pharmacology Integration: Type II diabetes
Liver Metformin Thiazolidinediones Pioglitazone Rosiglitazone

(+)
(-)
Uptake

GI problems
GI tract

Acarbose

(+)
Uptake Skeletal muscle

Blood Glucose (-)

(+)

Sulfonylureas Metformin (+) Acetohexamide Tolbutamide Pancreas: Secretes Hypoglycemia Chlorpropamide Insulin Glipizide GLP-1 analogs DPP-IV inhibition Glyburide Exenatide Sitagliptin

Adipose

Calcium RegulationSlide # 38
Estrogen

Plasma Ca2+
Ca2+

*
H+

Plasma phosphate

Renal reabsorption

PTH

Renal phosphate reabsorption

Ca2+ mobilization from bone

1-hydroxylase in kidney excess

25-hydroxylase in liver

Ca2+ absorption from GI Cortisol Stimulates

25-(OH)-D3

1,25-(OH)2-D3
GI phosphate absorption

7-dehydrocholesterol Pg 316

Inhibits

Sexual DifferentiationSlide # 39
MIH = Mllerian inhibiting hormone Undifferentiated gonad XXno SRY XY has SRY MIH Mllerian ducts Wolffian ducts Mllerian ducts T = Testosterone SRY = sex determining region of Y

Ovaries

Testes
T Wolffian ducts

Regress
Fallopian tubes, uterus, inner vagina Epididymis, vas deferens, seminal vesicles

Regress
Fallopian tubes, uterus, inner vagina Epididymis, vas deferens, seminal vesicles

Sexual DifferentiationSlide # 40
Testosterone
5 alpha-reductase

dihydrotestosterone (DHT)
Testes
DHT

Ovaries

No DHT
Undifferentiated organs

Clitoris, outer vagina, labia

Penis, scrotum, & prostate

MenopauseSlide # 41
ACTH Choles DHEA A Adrenal cortex Tamoxifen Raloxifene aromatase FSH/LH

Tumor Growth

Choles Test/A aromatase 17b-Estradiol

Blood
Ovary
Anastrozole Letrozole

DHEA

A
Adipose tissue

Estrone

Polycystic Ovarian SyndromeSlide # 42

PCOS
Hirsutism; irregular menstrual bleeding; chronic anovulation; obesity; insulin resistance; infertility Oral contraceptives Clomiphene: FSH LH to LH FSH

Adipose estrone

Pituitary

aromatase

Estradiol anovulation

Follicle maturation

Thecal hormone production

Adipose insulin Androgens

Ovaries

Thiazolidinediones; Metformin SHBG

Androgens Dexamethasone

Adrenal

Venous PulseSlide # 43
Atrial contraction PR interval No atrial contraction

Text on pg 124

Pathology Integration

Atrial pressure

by stiff right ventricle: Pulm Sten; Pulm regurg

Venous PulseSlide # 44
Bulging of the tricuspid

Text on pg 124

Atria relax

Pathology Integration

Venous PulseSlide # 45
Filling of the atria

Text on pg 124

Pathology Integration

Enhanced because of backflow of blood

Venous PulseSlide # 46
y-decent is associated with emptying of right atrium

Pathology Integration

Enhanced because of atrial engorgement

Blunted because of resistance