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Angiotensinogen
Angiotensin I (AI)
Angiotensin II (AII)
(ACE)
Renin
Aldosterone (Na+
and water retention)
Primary factors regulating Renin:
1. Perfusion pressure to the kidney stimulates; inhibits
2. Sympathetic stimulation to kidney viaBeta-1 receptor
3. Na+ delivery to the macula densa delivery stimulates; delivery inhibits
Primary factors regulating aldosterone:
1. Plasma [angiotensin II] (AII) stimulatesrelease
2. Plasma [K+] stimulates releasePrimary factors regulating AVP:
1. Plasma osmolarity stimulates release
2. Blood volume/pressure
inhibits release
Integration of Volume RegulationSlide # 1
RAAS
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SummaryEdemaSlide # 2
Primary causes of edema (High yield for exam)
Pc: FlowVasodilation; Venous pressureVenousobstruction; 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
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- +-70 mV
(Em)
[K+]OLow
[K+]iHigh
[Na+]OHigh
[Na+]iLow
[Cl-]OHigh
[Cl-]i
Low
Prot -
Prot -
Prot -
Prot -[Ca2+]iLow*
[Ca2+]OHigh
High YieldIonic EquilibriumSlide # 3
*-refers to cytosolic free calcium
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High YieldIonic EquilibriumSlide # 45 fundamental principles
1. Membrane po tential (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. Equi l ibr ium po tent ial :membrane potential that balanceschemical and electrical force across the membrane. In other
words, the membrane potential that results in no NET diffusion of
an ion. (Nernst equation)
4. Conduc tance (g) or permeabi l i ty:ease with which an ioncrosses the cell membrane. Determined by number of open
channels that allow the ion to pass through the membrane.
5. Driv ing force (net forc e):Resting membrane potential minus
equilibrium potential.
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Fast Sodium ChannelsSlide # 5
Open
Na+
Na+Na+
Positive membrane
potential and timeclose h-gate
h-gate
(inactivation)
M-gate
(activation)
Inactivated
Depolarization
opens M-gate
Closed at Em
Repolariztion
TTX; STX; Caine
Ca2+
Pharmacology
Integration
Tetrodotoxin (TTX)/Saxitoxin (STX)/Caine drugs
Outside
Inside
Ciguatoxin (CTX)/Batrachotoxin (BTX)
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Nerve DysfunctionSlide # 6
Alpha motor neuronSkeletal
muscle
Decreased excitability/Lack of conduction
Ion disturbances Hypokalemia ( gradient) Hypercalcemia (Na+
channels)
Demyelination
Guillain-Barr syndrome
(GBS)
Neuronal loss
ALS
Aging
Toxins/drugs
TTX/STX
Local anesthetics
Weakness; fatigue; ataxia;
hyporeflexia; paralysis; sensory deficit
Ion disturbances
Hyperkalemia
(
gradient) Hypocalcemia
(Na+ channels)
Increased excitabilityToxins/drugs 3,4-DAP; 4-AP
CTX/BTX
hypereflexia; spasms;
muscle fasciculations;tetany; tremors;
paresthesia; convulsionsCentral
demyelination
by MS
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Voltage-gated Ca2+
channel
Na+
K+
Ca2+
Na+
ACh
Nicotinic receptor Voltage-gated Na+
Depolarizing & non-
depolarizing blockers Myasthenia Gravis:autoimmune/congenital
Lambert-Eatonsyndrome:
autoimmune
Demyelination of GBS can block
action potential
AChE inhibitors
(organophosphates)
Botulinum toxin (Botox)
prevents release of ACh
Hyperkalemia/ hypocalcemia Hypokalemia/ hypercalcemia
TTX
STX
Latrotoxin
3,4-
DAP
4-AP
Neuromuscular Junction (NMJ)Slide # 7
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High Yield EKG ChangesSlide # 8
Path/Pharm
Integration
ST Elevation
Transmural infarction
Prinzmetal angina
ST Depression
Subendocardial ischemia
Classic (stable) angina
Hyperkalemia: Rate repol Sharp, spiked T wave
QT interval
Hypercalcemia
QT interval
Hypokalemia: Rate repol U waves
QT intervalHypocalcemia
QT interval
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Muscle DysfunctionSlide # 9
Alpha motor
neuron
Skeletal muscle
Decreased
force (weak) Muscular dystrophies
Disuse Atrophy
Aging
Protein wasting
Pompe
Malignant
hyperthermia (treat
with dantrolene)
Tetanus toxin
(glycine in spinal
cord)
Spasms/
contractures
Exercise-induced
McArdle
Exercise-induced
McArdle
NM block
TTX/STX
Local anesthetics
Botox
ALS
GBS
Severed nerve
Flaccidparalysis
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High Yield RelationshipsSlide # 10
Q =
DPR CO = HR X SV C = DP
DV
C
SVPP =R L
r4
T Pr
(LaPlace)
Pulse pressure (PP) = systolic - diastolic
DP R
MAP = 1/3 PP + diastolic pressure
Velocity = Q/CSA
P = height X density X
gravity
Uptake of O2
A V O2 differenceFlow =
Cardiac Index = CO/ body surface area (BSA)
Uptake of O2 = Flow X A V O2 difference
MAP = CO X TPR
Reynolds number = (velocity) (diameter) (density) / viscosity
EF = SV/EDV X 100
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Free Flow (Q)Slide # 11
P = 70P = 80
Q
DownstreamPressure
UpstreamPressure
Change R
here
Vasoconstrict
DP R
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Deeeeep
Thoughts Brain
= resistor
Arterioles are
resistors!!
Total resistance(TPR/SVR) is sum of
each resistor.
Think of each
resistor as a faucet.
Total resistance
(TPR/SVR) is
AFTERLOAD for
heart.
Must have an adequate
MAP to drive flow!!!!
P = Q X R
MAP = CO X TPR
Slide # 12
Cant have all
faucets open
simultaneously.
Vasoconstrictors
Sym (NE)alpha!!! Epialpha
AII & AVP
Alpha agonists
NE releasers
Reuptake blockers
Vasodilators
sym!!! EpiBeta-2
metabolism & NO Alpha blockers
NO releasers
CCB
K+ channel
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Low
Compliance
Water
ComplianceSlide # 13
DV = DP X C
High
Compliance
DP = CDV
C = DPDV
Water
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Venous Return is the flow of blood TO the heart.
Central blood volume is directly related to venous return.
Central blood
volume
(PRELOAD)
CVP and pulmonary wedge pressure are clinical markers ofcentralblood volume
Venous return is
DIRECTLY related to
blood volume and
INVERSELY relatedto venous
compliance
Blood volume in?Sympathetic stimulation
compliance, thus venous return
Pharm Integration:
Nitrates preferentially
dilate veins ( theircompliance)
What does an elevated CVP suggest?
Pump failure
Venous ReturnSlide # 14
Venous
return
blood volume; Venoconstriction
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MAP = CO X TPR
4 factors determine
1. HR ( CO exercise; COwith tachyarrhythmias)
2. Contractility (direct)
3. Afterload (inverse)
4. Preload (direct)
Directly related to venous return
Blood volume (direct)
Venous compliance (inverse)
Tone of arterioles
Sympathetic (alpha)
AII AVP
Epi (alpha/beta-2)
Metabolism
NO
Pharm integration
Whole Body CV RegulationSlide # 15
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Effect of GravityCompensationsSlide # 16
Venous Pooling
ventricular volume(sensed by cardio-
pulmonary
baroreceptors)
Reflex sympatheticnervous system
Sympathetic activation:
Constricts veins (Rec?)
HR/Inotropy (Rec?) Constricts arterioles (TPRRec?)
Path/PharmIntegration
Orthostatic intolerance
vascular volume Venodilators; alpha blockers
Denervated heart/ heart failure
Dysautonomias (diabetes mellitus)
Arterial baroreceptorsif MAP falls
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Anti-hypertensive
drugs
Short/Long Term MAP RegSlide # 17
Mean Arterial
Pressure
InhibitsStimulates
Baroreceptor activity
Sympathetic
activity
Contractility
TPRCardiac
output
Heart rateb1
a
b1 Veno-constrictiona
Stroke volumePreload
M2
Parasympathetic
activity
Urine volume
Blood volume
Renin
A II
b
VR
VRF-S
Aldo
Shock
Autonomic
drugs
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High Yield Application of Fick Principle
Cvo2Cao2Q
Cell
consumes
O2
VO2 = Q X (CaO2 CvO2)
Fick
O2 delivery = Q X CaO2
Q Extraction Venous O2 CaO
2with same Q & extraction Venous O
2
O2 extraction (by
the tissue)
O2
consumption
Slide # 18For any given O2
consumption, a
indelivery results in: 1)
possible hypoxic/ischemic
damage, & 2) a theamount of O2 in the veins
draining the tissue.
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Tip 2: Pressure/volume behind the defective valve
Systolic murmur: Mitral/Tricuspid insufficiency;
Aortic/Pulmonic stenosis Diastolic murmur: Mitral/Tricuspic stenosis;
Aortic/Pulmonic insufficiency
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
Valvular ProblemsSlide # 19
F A ti th R i t S t Slid #20
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Forces Acting on the Respiratory SystemSlide #20
Key forces to be aware of to understand ventilation
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)
Lung recoil: Force exerted by the alveoli; This is an INWARD
force and is inversely related to compliance.
T l P G di t Slid # 21
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Transmural pressure (PTM) gradient is the pressure
gradient across the wall of any tube or sphere.
PTM
= Pi
- Po
Po
Transmural Pressure GradientSlide # 21
Pi
Alveolus, airway, or blood vessel
IPP P l Bl d Fl Slid # 22
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Pg 147
IPPPulmonary Blood FlowSlide # 22
Inspiration
PTM = 0-5 = 5
Becomesmore
negative
RA in chest expands pressure so Q (VR)
Increased output delays
closing of pulmonic valve
(physiologic splitting of S2
)
PTM forpulmonary
vessels; their
volume increases
Increases pulmonary
vascular resistance
Flow to LH
MAP = CO X TPR
Inspiration decreases vagal outflow
to the heart, thus HR increases
(respiratory sinus arrhythmia)
Veins here are
unaffected
S V /Q Mi t h Slid # 23
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Severe VA/Q MismatchSlide # 23
1. Increased A a gradient
2. Increasing FIO2 helpful
Diagnostic signs:
PAO2 = (Patm 47) FIO2 (PACO2/R)
Flow from low VA/Qunits (
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Differential for Causes of HypoxemiaSlide # 24
Low PaO2
(hypoxemia)
A a gradient
FIO2 corrects
PaCO2 likely
elevated
Normal
Cause is
PAO2
Elevated
Increase FIO2
Doesnt
correct PaO2
Cause is right-
to-left shunts
Corrects
PaO2
VA/Q
mismatch
Diffusion
impairment
PAO2: calculate usingalveolar air equation or
use end-tidal PO2
H i Slid # 25
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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
R l ti hi /E ti f R l Slid # 26
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Relationships/Equations for RenalSlide # 26
GFR
RPF
FF =
FF impacts Pc!!! Filtered load = GFR X PXRate of excretion = UX X V
Transport = excretion filtered load
Renal
clearance =UX X V
PX
UPAH X VCPAH =
PPAH
ERPF =
Renal blood flow =1- Hct
ERPF
F t Aff ti GFR d FF Slid # 27
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Factors Affecting GFR and FFSlide # 27
Glomerularcap
pressure
Peritubularcap
pressure
Nephronplasma
flow
GFR FF
Constrict efferent Dilate efferent Constrict afferent Dilate afferent
U i A id Slid # 28
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Uric AcidSlide # 28
Pharmacology
Integration
Adenosine
Guanosine
Hypoxanthine
Guanine
Salvage
Xanthine
Uric Acid H+ + Urate-
Xanthine
Oxidase
Urate-
Urate-
Urate-Allopurinol
Biochemistry
IntegrationProbenecid
Lesch-Nyhan
80-90% of
urate isreabsorbed
in PT
UA
+
Precipitate
At low
tubular
pH
Gout
X
Ele ated Anion Gap MUDPILES Slide # 29
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Elevated Anion GapMUDPILESSlide # 29
L: Lactic acidosis
E: Ethylene glycol; Ethanol ketoacidosis
S: Salicylates; starvation ketoacidosis; sepsis
I: Iron; Isoniazid
U: Uremia (renal failure)
D: Diabetic ketoacidosis
P: Paraldehyde
M: Methanol
Normal Anion Gap HARD UP Slide # 30
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Normal Anion GapHARD UPSlide # 30
P: Pancreatic drainage (pancreatic fistula)
U: Ureteral diversion (ureterosigmoidostomy)
A: Acetazolamide
R: Renal tubular acidosis
D: Diarrhea
H: Hyperchloremia (Parental nutrition)
Acid Base Decision Tree Slide # 31
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Acid-Base Decision TreeSlide # 31
Compensation?
Osis?
(pH)
Compensation?
Cause of
the osis?
ACIDOSIS ALKALOSIS
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)]
Low
(Acidosis)
High
(Alkalosis)
Low Elevated
Respiratory MetabolicMetabolic Respiratory
Use Winters to
determine what
Paco2 should be
Determine if
acute (1:0.2) or
chronic (1:0.4)
Determine if
acute (1:0.1) or
chronic (1:0.4)
Paco2 0.7 torrfor every 1 mEq/L
in bicarb
Look at bicarb
Cause of
the osis?
Low Elevated
Look at bicarb
Properties of Receptors Slide # 32
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50
100
0[H]
%R
espons
e
E + S (ES) E + P H + R (HR) responsestimulus response
50
100
0[S]
Velocity(%o
fmax)
Michaelis-Menten
Km
Vmax: determined
by [E] & [S]
Properties of ReceptorsSlide # 32
[H] is
limiting
[S] is
limiting
[R] is onefactor
Properties of Receptors Slide # 33
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50
100
0Log [A]
%R
esponse
50
100
0[H]
%R
esponse
Properties of ReceptorsSlide # 33
H + R (HR) responsestimulus response A + R (AR) responsestimulus response
EC50
[H] is
limiting
[H] is
limiting
[R] is onefactor
Overview of AVP Pathophysiology Slide # 34
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Overview of AVP PathophysiologySlide # 34
Low
Dehydration(2O)
High
Primary Poly-dipsia (2O)
SIADH(1O)
Plasma AVP
POSM
UOSM< 1
POSM
UOSM> 1
LowHigh
LowHigh
Plasma osmolality
*Nephro DI
(1O)
Plasma AVP
POSM
UOSM< 1
POSM
UOSM> 1
Neuro DI*(1O)
Note: AVP=ADH
Metabolism Cortisol Slide # 35
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MetabolismCortisolSlide # 35
Glucose
G6-phos
Glucose
6-P
Glucokinase
Glyphos
GlycogenGly
synthase
PEPCK
Fructose 1,6-
bisphosphatase
PDH
(thiamine)
Acetyl CoAPyruvate
carboxylase
(biotin)
OAA
Lactate
LDH
Acetyl CoA
carboxylase
Malonyl CoA
TCA Ketones
FA
FA
synthase
Pyruvate
kinase
PFK-1 (via
PFK-2)
Pyruvate
AA
(alanine)
Cortisol
Cortisol
Insulin Glucagon Slide # 36
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Glucose
G6-phos
Glucose
6-P
Glucokinase
Glyphos
GlycogenGly
synthase
PEPCK
Fructose 1,6-
bisphosphatase
PDH
(thiamine)
Acetyl CoAPyruvate
carboxylase
(biotin)
OAA
Acetyl CoA
carboxylase
Malonyl CoA
TCA Ketones
FA
FA
synthase
Pyruvate
kinase
PFK-1 (via
PFK-2)
Pyruvate
AA
(alanine)
Insulin stimulates
Glucagon stimulates
InsulinGlucagonSlide # 36
Urea
Diabetes Mellitus Slide # 37
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Pharmacology Integration: Type II diabetes
GI tract Blood Glucose
Pancreas: Secretes
Insulin
Liver
Sulfonylureas
Acetohexamide
TolbutamideChlorpropamide
Glipizide
GlyburideGLP-1 analogs
Exenatide
Acarbose
X
Thiazolidinediones
Pioglitazone
RosiglitazoneGI
problems
Hypoglycemia
DPP-IV inhibition
Sitagliptin
(+)
Uptake
Skeletal
muscle
Adipose
Uptake
Metformin
(-)
(-)Metformin
(+)
(+)
(+)
Diabetes MellitusSlide # 37
Calcium Regulation Slide # 38
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Pg 316
Calcium RegulationSlide # 38
Inhibits
Stimulates
Plasma Ca2+Plasma
phosphate
Renal Ca2+
reabsorption
Ca2+ mobilization
from bone
Ca2+ absorptionfrom GI
PTH
7-dehydro-
cholesterol
25-(OH)-D3
1,25-(OH)2-D3
excess
1-hydroxylase
in kidney
Renal phosphate
reabsorption
25-hydroxylase
in liver
GI phosphateabsorption
H+
Cortisol
Estrogen *
Sexual Differentiation Slide # 39
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Sexual DifferentiationSlide # 39
Wolffian
ducts
Mllerian
ducts
Wolffian
ducts
Mllerian
ducts
Fallopian
tubes,
uterus, inner
vagina
Epididymis,
vas
deferens,
seminalvesicles
Epididymis,
vas
deferens,
seminalvesicles
T = Testosterone
SRY = sex determiningregion of Y
MIH = Mllerian inhibiting
hormone
Ovaries
Fallopian
tubes,
uterus,
inner vagina
XY has
SRY
XXno
SRY Testes
TMIH
Regress Regress
Undifferentiated
gonad
Sexual DifferentiationSlide # 40
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Sexual DifferentiationSlide # 40
Ovaries Testes
Undifferentiated
organs
DHT
Clitoris, outer
vagina, labia
Penis,
scrotum, &
prostate
No
DHT
Testosterone dihydrotestosterone (DHT)5 alpha-reductase
MenopauseSlide # 41
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MenopauseSlide # 41
Test/A
17b-Estradiol
CholesCholes
Adipose tissue
Adrenal cortexBloodA
DHEA
FSH/LHACTH
aromataseEstrone
aromatase
Ovary
DHEA A
TumorGrowth
Anastrozole
LetrozoleTamoxifen
Raloxifene
Polycystic Ovarian SyndromeSlide # 42
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Polycystic Ovarian SyndromeSlide # 42
PCOSHirsutism; irregular menstrual bleeding; chronic anovulation; obesity;
insulin resistance; infertility
Thecalhormone
production
Adipose estrone
LH
FSHPituitary
Folliclematuration
aromatase Estradiolanovulation
Androgens
Adrenal
Adipose Ovaries
Androgens
Oral contraceptives
to LH
Thiazolidinediones;
Metformin
insulin
SHBG
Clomiphene: FSH
Dexamethasone
Venous PulseSlide # 43
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Venous PulseSlide # 43
No atrial contraction
Pathology
Integration
Atrial pressure
Atrial
contraction
PR interval
Text on
pg 124
by stiff right ventricle: Pulm Sten;Pulm regurg
Venous PulseSlide # 44
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Venous PulseSlide # 44
Atria relax
Pathology
Integration
Bulging of
the tricuspidText on
pg 124
Venous PulseSlide # 45
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Venous Pulse Slide # 45
Pathology
Integration
Filling of the
atria
Enhanced because of
backflow of blood
Text on
pg 124
Venous PulseSlide # 46
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Venous Pulse Slide # 46
Pathology
Integration
Blunted because
of resistance
Enhanced because of
atrial engorgement
y-decent is
associated
with emptyingof right atrium
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