Cardio Flashcards
[Cardiovascular Embryology] 1. Describe vitelline system for blood cell development 2. What happens to: A. R vitelline vein B. L vitelline vein C. R umbilical vein D. L umbilical vein E. Anterior cardinal vein F. Posterior cardinal veins
- Chorion (membrane that is part of the amniotic sac) establishes connections with umbilical vessels, which establishes connections with vitelline vessels, which establishes connections with umbilical vesicle
- vitelline vessels are yolk sac equivalent - source of blood cells
- All venous drainage (cardinal, vitelline, umbilical veins) into primordial heart is through sinus venosus
- paired dorsal aorta supply the body (later fuse and become descending aorta)
- umbilical arteries return deoxygenated blood to the placenta
2.
A. R vitelline vein –> hepatic vein
B. L vitelline vein –> degrades
C. R umbilical vein –> degrades
D. L umbilical vein –> remains
E. Anterior cardinal vein –> SVC, jugular, subclavian
F. Posterior cardinal veins –> IVC and azygos
[Cardiovascular Embryology]
- Different body parts that are responsible for fetal erythropoiesis
- Different variants of hemoglobin during development
1. Young Liver Synthesizes Blood Yolk sac (3-8 weeks) Liver (6 weeks - birth) Spleen (10-18 weeks) Bone marrow (18 weeks - adult)
- Alpha Always; Gamma goes; Becomes Beta
Fetal hemoglobin = HbF –> alpha2gamma2
Adult hemoglobin = HbA –> alpha2beta2
HbF oxygen dissociation curve shifted left for HbF –> higher affinity for 02 bc of weaker binding to 2,3-BPG –> can extract 02 across placenta from maternal HbA
[Cardiovascular Embryology] Embryologic Derivatives 1. Aortic sac 2. Truncus arteriosus 3. Bulbus cordis 4. Primitive ventricles 5. Primitive atria 6. Sinus venosus (L and R horns) 7. Primitive pulmonary veins 8. Cardinal vein (R)
- Aortic sac –> pharyngeal arches
- Truncus arteriosus –> ascending aorta and pulmonary trunk
- Bulbus cordis –> outflow tract (smooth part) of LV and RV
- Primitive ventricles –> trabeculated part of L and R ventricles
- Primitive atria –> trabeculated part of L and R atria
- Sinus venosus
A. L horn –> coronary sinus
B. R horn –> smooth part of RA - Primitive pulmonary veins –> smooth part of LA
- Cardinal vein (R) –> SVC
[Cardiovascular Embryology]
Describe heart morphogenesis
1. Formation of tubular heart
2. Formation of septated heart
Heart = 1st functional organ in vertebrates, beats spontaneously by 4th week
- Formation of tubular heart: Heart tubes begin in a horseshoe shape - superior to mouth and ventral to the intraembyronic coelom (future pericardial, pleural, peritoneal cavities)
- as head grows, the heart tubes fold ventrally and trap the foregut via the two dorsal aorta –> now head and mouth are superior, pericardial cavity is anterior
- Heart tubes approach each other in midline –> venous drainage develops
- septum transversum (future diaphragm) separates pleural space from peritoneal space - Formation of septated heart: loops to establish left-right polarity (3.5 weeks), needs cilia to rotate properly
- AV endocardial cushions invaded by neural crest cells which organize tissue movement –> endocardial cushions fuse together in dorsal-ventral direction –> create separated left and right canals (circulations)
[Cardiovascular Embryology]
List neural crest cell derivatives (from neuroectoderm)
PNS (dorsal root ganglia, cranial nerves, autonomic ganglia, Schwann cells) Melanocytes Chromaffin cells of adrenal medulla Parafollicular (C) cells of thyroid pia and archnoid mater bones of skull odontoblasts aorticopulmonary septum endocardial cushions
[Cardiovascular Embryology]
Kartagener’s syndrome
Kartagener’s syndrome - rare, autosomal recessive disorder; primary ciliary dyskinesia due to defects in dynein
Triad:
1. situs inversus; dextrocardia - heart points R instead of L
2. chronic sinusitis
3. bronchiectasis (bronchial tubes damaged/enlarged)
CV system functions normally
- also infertility
[Cardiovascular Embryology]
Describe atrial septum development
- Septum primum grows towards endocardial cushions –> narrows foramen primum
- Foramen secudum first forms in septum primum as small hole
- Septum secundum develops as foramen secundum maintains R–>L shunt
- Septum secundum expands and covers most of foramen secundum (residual = foramen ovale)
- Remaining portion of septum primum forms valve of the foramen ovale
- Septum secundum and septum primum fuse to form atrial septum
- Foramen ovale closes and fuses after birth bc of increased LA pressure (blood begins to flow from lungs to the left atrium)
[Cardiovascular Embryology] Describe atrial septal defects (ASD): 1. Patent foramen ovale 2. Ostium secundum type 3. Ostium primum type
- Pathology
ASD: LA–> RA shunt (non-cyanotic babies)
- Patent foramen ovale -NOT a true ASD- failure of septum primum and septum secundum to fuse after birth; in 25% of people and usually left untreated
- no true hole because primum can cover hole of the secundum - Ostium secundum type (90% of ASDs) - inadequate growth of septum primum or secundum
- Ostium primum type (5% of ASDs) - septum primum does not fuse with endocardial cushion; seen in Down syndrome, associated with AV valve defects
- Pathology - can lead to paradoxical emboli (venous thromboemboli that enter systemic arterial circulation)
Embolus (from leg, pelvis) passes through ASD –> LA –> LV –> CNS –> stroke
*embolic stroke + blood clots –> think hole in the heart (bc normally embolus causes PE, for a stroke the clot has to be able to move to the brain)
- with age (lungs getting too much blood for too long) –> pulmonary hypertension and reversal of shunt (like fetal circulation, from R–>L
- Right heart enlargement (hypertrophy) –> RV heave
- fixed S2 splitting
[Cardiovascular Embryology]
- Describe ventricular septum development
- Describe ventricular septal defect
- Muscular interventricular septum forms = opening called interventricular foramen
- Aorticopulmonary septum (neural crest cell derivatives) rotates and fuses with muscular part –> forms membranous interventricular septum and closes the foramen
- Growth of endocardial cushions separates atria from ventricles and contributes to both atrial septation and membranous portion of the interventricular septum
* aorta starts in back, ends up in front, pulmonary starts in front and ends up in back - VSD: LV –> RV shunt (non-cyanotic babies)
- most common congenital heart defect, most commonly occurs in membranous septum
- increased pulmonary blood flow –> LV volume overload –> LV eccentric hypertrophy
- harsh holosystolic murmur with high -moderate pitch; loudest at tricuspid with L to R shunt;
- over time can lead to pulmonary HTN and Eisenmenger’s syndrome
[Cardiovascular Embryology]
Describe the 5 Terrible T’s aka the etiologies behind “blue babies”
Blue babies due to R–>L shunt (Deoxygenated blood mixing with oxygenated blood) *most common cyanotic congenital condition is Tetralogy of Fallot
5 T’s of cyanotic CHD:
- Persistent Truncus arteriosus - 1 joint vessel instead of normal pulmonary artery and aorta
- due to abnormal neural crest cell migration, associated with 22q11 syndromes - Transposition of great vessels - aorta rises from RV, pulmonary artery from LV (switched) –> circulations in parallel (not series)
- need to maintain PDA through PGE
- associated with diabetic mother - Tricuspid atresia - complete absence of tricuspid valve –> undersized or absent right ventricle
- Total anomalous pulmonary venous return (TAPVR) - oxygenated blood returns back to the RA instead of the LA –> closed loop
- Tetralogy of Fallot: A) VSD B) overriding aorta (shifted over RV and the VSD as well as LV) C) RV hypertrophy D) pulmonary outflow tract stenosis most important
- due to abnormal neural crest cell migration –> displacement of interventricular septum anteriorly –> A-D result in R to L shunt
- kids squat to increase SVR (i.e. TPR) –> increased afterload –> increase pressure in LV –> reverse R to L shunt
- findings: clubbing of fingers/toes, “boot shaped” heart on CXR
[Cardiovascular Embryology]
1. Difference between blue babies and blue kids and the conditions that cause each
1A. Blue babies (Cyanotic at birth): R–> L shunts so deoxygenated blood reaches systemic circulation –> cyanosis
-due to: Tetralogy of Fallot (most common), Truncus arteriosus, Tranposition of great vessels, Tricuspid atresia, Total anomalous pulmonary venous return (TAPVR)
B. Blue kids (Acyanotic at birth): L–> R shunt so oxygenated blood is still being circulated, but the lungs are overloaded –> increases pulmonary venous return –> pulmonary HTN (bc right side cannot deal with high volume/pressure situations) –> when R side pressure is high enough, reverses shunt to R –> L (Eisenmenger’s syndrome)
- due to:
i. Volume overload - ASD, VSD, and PDA
ii. Pressure overload - aortic stenosis, pulmonic stenosis, aortic coarctation - treatment contraindicated once Eisenmenger’s develops
[Cardiovascular Embryology]
I. Describe valve development and the associated anomalies
I. Aortic/pulmonary valves - derived from endocardial cushions of outflow tract
Mitral/ tricuspid valves - derived from fused endocardial cushions of AV canal
Valvular anomalies:
A. atretic/stenotic/regurgitant e.g. tricuspid atresia
B. displaced e.g. Ebstein’s anomaly (valve is displaced downwards –> right ventricle is small); associated with lithium treatment for bipolar disorder in pregnant women
[Cardiovascular Embryology]
List aortic arch derivatives
1st arch –> part of maxillary artery (1st is maximal)
2nd arch –> stapedial artery, hyoid artery (S for Second)
3rd arch –> common carotid artery, proximal part of internal carotid artery (C is 3rd letter of alphabet)
4th arch –> (L) aortic arch ( R) proximal part of right subclavian artery
5th arch –> N/A (vestigial)
6th arch –> proximal part of pulmonary artery, (L) ductus arteriosus (degrades on R, becomes ligamentum arteriosum)
- L recurrent laryngeal nerve loops around L ductus arteriosus, R nerve loops around R subclavian artery
[Cardiovascular Embryology]
I. Describe fetal circulation
II. Describe the 3 important fetal shunts
III. What happens at birth and patent ductus arteriosus
A. How to close PDA
B. PDA murmur
I. Highly oxygenated blood from umbilical vein –> IVC (via ductus venosus) –> RA –> LA (via foramen ovale) –> LV –> ascending aorta –> pumped to body –> deoxygenated blood goes back into heart through SVC –> RA –> RV -> pulmonary artery –> descending aorta (via ductus arteriosus) –> iliac arteries –> umbilical arteries –> to placenta for oxygenation
II. Shunts
- Ductus venosus - 02 blood entering fetus from umbilical vein –> IVC (bypass hepatic circulation)
- Foramen ovale - oxygenated blood from IVC shunted from RA –> LA (bypass the lungs)
- Ductus arteriosus - deoxygenated blood from pulmonary artery –> descending aorta –> back to placenta for oxygenation (higher oxygenated blood can go to brain)
III. At birth, infant takes a breath –> decreased resistance in pulmonary vessels -> increased left atrial pressure –> foramen ovale closes
increase in 02 (From respiration) and decrease in prostaglandins –> closure of patent ductus arteriosus PDA
A. indomethacin blocks PG synthesis –> closes PDA (close even small PDAs to prevent infective endocarditis)
- PGE1 and E2 keep PDA open
B. PDA: continuous machine like murmur loudest at S2; due to congenital rubella or prematurity –> L side volume overload and dilatation, best heard at left infraclavicular area
[Cardiovascular Embryology] List fetal-postnatal derivatives 1. Umbilical vein 2. Umbilical arteries 3. Ductus arteriosus 4. Ductus venosus 5. Foramen ovale 6. Allantois
Embryological remannts of fetal circulation
- Umbilical vein –> ligamentum teres hepatis
- Umbilical arteries –> medial umbilical ligaments
- Ductus arteriosus –> ligamentum arteriosum
- Ductus venosus –> ligamentum venosum
- Foramen ovale –> fossa ovalis
- Allantois –> urachus - median umbilical ligament
[Cardiovascular Embryology]
- Differentiate RCA vs LCA anatomy supplied and relate to the EKG leads
- Differentiate Right vs Left dominant circulation
- Differentiate pericardial vs cardiac pain
- RCA = posterior heart –> RA, RV, SA/AV nodes (inferior leads II, III, aVF and posterior leads V1-V3 reciprocal changes bc technically there are no posterior leads)
LCA = anterior heart –> LA, LV, His-Purkinje system, anterior 2/3 interventricular septum (anterior leads V1-V4; left circumflex correlates to left lateral leads I, aVL, V5, V6)
- Right dominant circulation (85% pop) - RCA supplies posterior descending branch of coronary artery i.e. posterior interventricular artery –> which supplies posterior 1/3 interventricular septum, AV node, and posterior wall ventricles
- Pericardial pain referred to C3-C5 dermatomes (shoulder, neck area)
Cardiac pain referred to chest through visceral pericardial afferents that return to T1-T5 via SNS
[Cardiovascular Physiology]
- Describe properties of cardiomyocytes
- Describe the steps of the myocardial action potential
- What is the main difference between excitation-contraction coupling in myocytes
- Cardiac muscle - automatic, involuntary, striated tissue containing uninuclear cells connected by intercalated discs (gap junctions, desmosomes, and tight junctions) –> depolarizing one cell leads to all cells being depolarized
- Myocardial action potential
Phase 0: Rapid upstroke –> rapid Na+ influx through fast channels –> depolarization
Phase 1: Na+ channels inactivated, fast K+ channels open –> K+ efflux –> initial repolarization returns transmembrane potential to 0mV
Phase 2: Plateau because K+ Efflux balanced by Ca2+ influx through slow L channels–> Ca2+ influx triggers Ca2+ release from sarcoplasmic reticulum + myocyte contraction
Phase 3: Rapid repolarization –> Ca2+ channels close and rapid K+ efflux through slow channels
Phase 4: resting potential at -90 mV–> high K+ permeability - Calcium-mediated calcium release
additional Ca2+ that comes into cell during plateau phase prolongs cross-bridge cycling time –> stimulates release of more Ca2+ from sarcoplasmic reticulum
[Cardiovascular Physiology] Define and describe relationships between: 1) stroke volume 2) end diastolic volume 3) end systolic volume 4) cardiac output
Describe Frank Starling Curve
1) stroke volume SV- how much blood is pumped out by LV in one contraction; marker of cardiac function
SV = EDV - ESV
2) end diastolic volume EDV - preload (volume of blood filling the heart); dictates extent of overlap between actin and myosin cardiac muscle fibers
3) end systolic volume ESV- volume of blood left in heart after contraction
4) cardiac output CO- amount of blood the heart pumps out each minute
CO = SV x HR
Relationship between SV and EDV is Frank-Starling ventricular function curve: Stroke volume of the heart increases in response to an increase in the volume of blood filling the heart (EDV) when all other factors remain constant
What happens to SV under the following conditions:
1) increased preload
2) increased afterload
3) increased inotropy (contractility) of the heart
What factors increase or decrease 1, 2, 3 incl the effect of digoxin
1) increased preload –> Increased EDV and SV
A. Preload ~ ventricular EDV = diastolic pressure that distends the ventricle–> increased by valve defects e.g. aortic stenosis/regurgitation
B. decreased by venodilators e.g. nitroglycerin
2) increased afterload –> increased ESV –> decreased SV
A. afterload ~ mean arterial pressure = impedance against which ventricle must eject –> increased by HTN (due to increased peripheral vascular resistance, due to increased arteriolar tone)
B. decrease by vasodilators e.g. hydralazine
`ACEIs and ARBs decrease both preload and afterload
3) increased inotropy (contractility) of the heart –> decreased ESV –> increased SV
A. contractility increased with: increased intracellular Ca2+, decreased extracellular Na+ (impacts Na+/Ca2+ antiporter), catecholamines (SNS tone), and digoxin/digitalis, from foxglove plant (competes for binding with K+ to Na+/K+ ATPase –> therefore Ca2+ cannot leave myocyte via Na/Ca exchanger; use leads to xanthopsia or yellow color vision)
- hypokalemia leads to increased chance of digoxin toxicity
B. contractility decreased with: beta blockage, heart failure, acidosis, hypoxia, and Ca2+ channel blocker e.g. verapimil, amlodipine
[Cardiovascular Physiology]
Describe autonomic control of cardiac output
Describe steps in the Beta1 receptor stimulation of inotropy
- PSNS - reduces HR via vagus nerve (cholinergic M2 receptors on SA and AV nodes)
* M2 = muscarinic –> slow, uses receptor binding - SNS - increases HR and contractility via adrenergic Beta1 receptors on SA, AV nodes and cardiomyocytes
Catecholamine stimulation of contractility via Beta1 receptors:
- Phosphorylation of L-type Ca2+ channels –> remain open longer
- Phosphorylation of proteins in sarcoplasmic reticulum –> increased release of Ca2+
- Phosphorylation of myosin –> increases myosin ATPase –> increases crossbridge cycling
- Phosphorylation of Ca2+ pumps in SR –> increase speed of calcium re-uptake and relaxation
[Cardiovascular Physiology] 1. What is Laplace's Law and connection to MV02 2. Describe types of cardiac hypertrophy A. Concentric vs Eccentric B. Physiologic vs Pathologic
- Laplace’s Law: Wall tension = (PxR)/2 x Thickness
MyoCARDial oxygen consumption (MVO2) is directly related to wall tension and increased by:
Contractility
Afterload
Rate of heart
Diameter of ventricule - Cardiac hypertrophy
A. Concentric vs Eccentric
i. Concentric - due to pressure overload (sarcomeres added in parallel) –> increased wall stress –> LV wall thickens and radius decreases in attempt to reduce stress
ii. Eccentric - due to volume overload (sarcomeres added in series) –> increase in blood volume –> increase in chamber radius
B. Physiologic vs Pathologic
i. Physiologic - reversible
Concentric due to weight-lifting
Eccentric due to pregnancy, endurance training
ii. Pathologic - irreversible
Concentric due to chronic HTN, aortic stenosis
Eccentric due to valvular regurgitation
[Cardiovascular Physiology]
- Relate CO and MAP
- What happens to CO during exercise?
- Fick Principle of calculating CO
- MAP = Mean arterial pressure (average arterial pressure during cardiac cycle), TPR = total peripheral resistance (aka systemic vascular resistance SVR)
MAP = CO x TTR –> perfusion pressure seen by organs
MAP = 2/3 (diastolic P) + 1/3 (systolic P) - When you exercise, SNS vasodilates muscle vascular beds / arteries (via Beta2 adrenergic receptors) to increase blood flow –> blood pressure decreases
to compensate, need to increase CO (=SVxHR)
- early stages of exercise –> both SV and HR increase
- late stages/maximal exercise –> SV plateaus, CO maintained by increased HR only - Fick principle:
CO = rate of 02 consumption / (arterial 02 content - venous 02 content) [L/min]
*02 content = (1.34 x Hb x Sa02) + (0.003 x Pa02) *mostly dependent on [Hb]
[Cardiovascular Physiology] 1. Define resistance using Poiseuille's Equation 2. Difference in resistance bw types of blood vessels and organs 3. Autoregulation of following organs: A. heart B. brain C. kidneys D. lungs E. skeletal muscle F. skin
- Poiseuille equation: Resistance = 8n(viscosity) x length / pir^4
- resistance mostly determined by arteriolar tone (blood volume determined by venous tone)
- viscosity depends on hematocrit (RBCs:total blood volume) - Blood vessels arranged in series (resistances additive); greatest drop in pressure across bv with greatest resistance –> arterioles
Circulations in body organs arranged in parallel –> organ with lowest resistance gets most flow; can dilate/constrict to control flow - Autoregulation
A. heart - local vasodilators (C02, adenosine, NO)
B. brain - local vasodilators (C02, H+)
C. kidneys - myogenic, tubuloglomerular feedback
D. lungs - hypoxia causes vasoconstriction *OPPOSITE in all other organs
E. skeletal muscle - local vasodilators (lactate, adenosine, K+)
F. skin - sympathetic stimulation to maintain temperature control
[Cardiovascular Physiology]
- Equation for net filtration pressure
- Causes of edema
- Net filtration pressure = Pnet = (P cap + Pi if) - (P if + Pi cap)
Pnet = Jv (net fluid flow) / Kf (filtration constant for capillary permeability) - Edema - excess fluid outflow into interstitium (more than can be captured by the lymph)
Pitting edema caused by:
A. increased capillary pressure P cap e.g. heart failure
B. Decreased plasma proteins Pi cap e.g. nephrotic syndrome, liver failure
C. Increased capillary permeability Kf e.g. toxins, infections, burns
D. Increased interstitial fluid colloid osmotic pressure Pi if e.g. lymphatic blockage
[Cardiovascular Physiology] 1. Describe the cardiac output curves 2. Describe the effects on curves + examples of: A. inotropy B. venous return C. total peripheral resistance
- Cardiac output (y axis) increases with right atrial pressure (x axis) until a maximum
- Venous return decreases with increased RAP until it hits 0 –> mean systemic pressure (mean pressure in circulatory system when blood can redistribute equally)
- CO = venous return at operating point (equilibrium) - In general, v hard to isolate these factors bc autonomic nervous system affects them all
A. inotropy - shifts cardiac output curve only
More inotropy –> shifts upwards e.g. digoxin
Less inotropy –> shifts downwards e.g. uncompnesated heart failure, narcotic OD
B. venous return - shifts venous return curve only
More volume, venous tone –> shift upwards e.g. blood infusion
Less volume, venous tone –> shift downwards e.g. hemorrhage, venodilators
C. total peripheral resistance - redistribution of blood to venous side when decreased, vice versa
Increased TPR –> decreased slope of venous return and CO curves e.g. isolated arteriolar venoconstriction
Decreased TPR –> increased slope of venous return and CO curves e.g. exercise, AV shunt
[Cardiovascular Physiology] 1. Describe cardiac cycle illustrated on pressure-volume loop 2. Describe isolated effects of: A. increased preload B. increased afterload C. increased contractility
- LV pressure on Y axis, LV volume on X axis
cardiac cycle needs to lie between end systolic PV relationship ESPVR (contractility) and end diastolic PV relationship EDPVR (compliance)
[SEE PICTURE OF CARDIAC CYCLE CURVE]
2A. increased preload - EDV increases, but ESV stays the same –> SV increases
B. increased afterload - ESV increases –> SV decreases
C. increased contractility - ESV decreases –> SV increases
[Cardiovascular Physiology]
- How does systolic heart failure affect Frank-Starling curve?
- Describe the 3 main types of systolic heart failure
- Differentiate with diastolic heart failure
- systolic heart failure - due to decreased inotropy/contractility or pressure overload –> reduced ejection fraction
- decreased slope (SV is y axis and EDVP/preload is x axis) –> decrease in SV for same level of preload - 3 main types of systolic heart failure:
A. myocardial infarction - loss of myocardium (irreversible membrane disruption)
B. alcoholism - ventricular dilatation due to cardiomyopathy
C. pressure overload - Diastolic heart failure - stiff ventricle inhibits ventricular filling –> EF normal or elevated
[Cardiovascular Physiology] 1. Describe the heart sounds S1 S2 S3 S4
2. Describe splitting A. physiologic B. Wide C. Fixed D. Paradoxical
- Heart sounds
S1 - mitral and tricuspid valve closure; heard loudest at mitral area
S2 - aortic and pulmonary valve closure; heard loudest at left sternal border
S3 gallop “Kentucky”- (abnormal) occurs after S2 early diastole during rapid ventricular filling; associated with increased filling pressures and volume overload (eg heart failure) but can be normal in children and pregnant women
S4 gallop “Tennessee”- (abnormal) “atrial kick” in late diastole right before S1 due to high atrial pressure; associated with ventricular hypertrophy when LA pushes against stiff LV - Splitting
A. Physiologic - (expiration) A2 closes before P2 - but close enough that its 1 sound
(inspiration) chest expands –> intrathoracic pressure becomes more negative –> ↑ venous return –> ↑ RV filling + increased capacitance –> takes longer to empty –> delayed pulmonic valve closure = delayed P2
B. Wide - A2/P2 splitting during expiration and inspiration (worse on inspiration) due to delayed pulmonic valve closure due to pulmonic stenosis, right BBB
C. Fixed - A2/P2 splitting that is constantly wide during expiration and inspiration due to ASD
D. Paradoxical - (expiration) P2 occurs before delayed A2
(Inspiration) single sound due to delayed aortic valve closure due to aortic stenosis, left BBB
[Cardiovascular Physiology]
Cushing reflex in brain injury
Cushing reflex - terminal stages of acute head injury:
triad of HTN, bradycardia, and respiratory depression
cerebral injury –> increased intracranial pressure –> constricts arterioles in brain –> cerebral ischemia –> Activates SNS –> increased HR and contractility –> increases BP (to ensure blood and 02 delivery to the brain) –> but increased BP activates baroreceptors –> Activates PSNS –> bradycardia
- only get part of baroreceptor reflex bc SNS is dominant in vasculature, while PSNS is dominant in heart and overrides SNS tachycardia drive
[Atherosclerosis]
1. Where does atherosclerosis most commonly occur (types of vessels, vessel sites)?
2. Functions of endothelial cells
3. First step in devlpt of atherosclerosis
A. Mechanical injury
B. Chemical injury
4. Effect of injury
- Most common vessels - large and medium-sized muscular arteries
Most common sites - bifurcations, branch points, regions of high curvature - Endothelial cells (ECs) line up in direction of blood flow; modulate immune response, have anticoagulant functions, release vasodilators (e.g. NO, prostacyclin), anti-hypertrophic properties
- First step - endothelial dysfunction / injury
A. mechanical endothelial injury: at branch points, laminar flow disturbed –> flow becomes turbulent, with low flow areas –> disturbed shear leads to high EC turnover, poor alignment, inflammatory genes/altered gene expression, high permeability, oxidative stress
*problem is exacerbated by high pressure (eg HTN)
B. Chemical injury e.g. dyslipidemia (direct correlation bw plasma cholesterol and heart disease), cigarette smoking, diabetes - Both mechanical + chemical injury –> alter endothelial behavior so they are no longer anti-inflammatory, but become pro
- alter substances to be vasoconstrictive
- recruit leukocytes
- release inflammatory cytokines
- produce ROS, become prothombotic
[Atherosclerosis]
- What happens after endothelial dysfunction?
- Exogenous pathway of lipid absorption
- Endogenous pathway
- Endothelial dysfunction allows lipoprotein entry and modification in subendothelial space; principal culprits are LDLs bc of their overflow pathway (high proportion of cholesterol, contain ApoB100)
- Exogenous (small intestine) - lipids (cholesterol, fat, monoglycerides, etc) in food packaged into bile salt micelles –> taken up by intestinal epithelial cell –> broken down into cholesterol esters, phospholipids, and triglycerides –> packaged into chylomicrons which are TG-rich and have ApoB-48 –> released into lymph –> acquire ApoA, ApoE, ApoC from HDLs in the bloodstream –> binds to lipoprotein lipase and offloads TGs to muscle and fat in the form of FFAs –> chylomicron remnants go back to liver and taken up
- Endogenous pathway (liver) - VLDLs composed of TGs and cholesterol, packaged with ApoB-100 –> circulate in blood and interact with HDLs –> acquire ApoE, ApoC, and cholesterol esters –> binds to lipoprotein lipase and offload TGs to muscle and fat in the form of FFAs –> VLDL remnants return to liver –> 50% cleared via ApoE receptor and 50% processed by hepatic triglyceride lipase and LPL to form LDL
* HDL involved in reverse cholesterol transport - transfer of cholesterol from VLDL, IDL, LDL in periphery to liver
[Atherosclerosis] - Inherited disorders 1. Familial hypercholesterolemia A. Inheritance B. Defect C. Plasma lipid pattern
1A. Familial hypercholesterolemia - autosomal dominant (incompletely dominant)
B. Defects: most commonly LDL receptor mutation (300+ mutations IDed)
- also Apo-B100, PCSK9 mutations
C. Homozygous FH - severely elevated cholesterol levels >600 mg/dL
- Heterozygous FH - elevated cholesterol > 250mg/dL
- normal total cholesterol level (incl LDL and HDL): <200 mg/dL
Other genetic dyslipidemias (FOR STEP REVIEW): familial combined hyperlipidemia, Type III hyperlipidemia, ApoC-II deficiency –> atherosclerosis leads to high CRP levels (marker of inflammation)
longer and lower the reduction in circulating LDL-cholesterol –> lower incidence of coronary heart disease e.g. MI
[Atherosclerosis]
What are the consequences of lipoprotein entry into the endothelial cells? How does it contribute to atherosclerotic process
Endothelial dysfunction –> Lipoprotein entry –> Inflammation –> leukocyte recruitment –> SCM and ECM proliferation
After lipoproteins (LDL particles) enter cell, they become oxidized or glycated by the inflammatory processes going on in EC –> recognized by scavenger receptors on macrophages also drawn to the area by the injury –> inflammasome activation of inflammatory process –> forms foam cells (fat-laden macrophages)
Smooth muscle cells SMC in the media become activated as a result of the inflammation –> migrate into the intima
- injury response – body is recognizing atherogenesis as damage/injury and tries to contain it via a fibrous cover –> process makes vessel more and more narrow (“Fatty streak”) but does stabilize atherogenesis and prevents thrombus –> becomes calcified (do not know etiology)
Fatty streak –> plaque progression –> plaque obstructive plaque (Stable angina) –> disruption (unstable angina)–> thrombus (MI/heart attack)
[Atherosclerosis] 1. List non-modifiable risk factors 2. List modifiable risk factors 3. Differentiate primary vs secondary prevention 4. Novel biomarkers that can predict risk A. C-reactive protein B. Lipoprotein a C. homocysteine
Risk factors for atherosclerosis are multiplicative
- List non-modifiable risk factors
- advanced age
- M»F
- heredity - List modifiable risk factors
- dyslipidemia (elevated LDL)
- smoking
- HTN
- diabetes, metabolic syndrome
- lack of physical activity - Primary - delaying/preventing onset of the disease
Secondary - patient already has the problem - goal is to prevent progression of disease - Biomarkers
A. C-reactive protein (CRP) - marker of inflammation associated with CAD –> released from liver in response to inflammatory cytokines
B. Lipoprotein a - linked to ApoB-100, structurally related to prothrombotic plasminogen; size and concentration is genetically determined
C. homocysteine - independent risk factor for cardiovascular disease
[Acute Aortic Syndromes]
- Describe microscopic anatomy of aorta
- Role of fibrillin-1 and deficiency
- Properties of the aorta
- Microscopic anatomy:
A. Intima - endothelial cells overlying internal elastic lamina
B. Media - smooth muscle cells and extracellular matrix of collagen (Strength) and elastic fibers (distension)
- lamellar unit - can withstand high pressure and distend in response –> allows pressure to evenly flow to extremities
C. Adventitia - vaso vasorum (blood vessels) - Fibrillin-1 - glycoprotein that helps maintain structural integrity of aortic wall and valve leaflets by tethering smooth muscle cells to elastin/collagen matrix
- deficiency –> VSMC detachment from matrix –> loss of ECM structural integrity –> Marfan syndrome - Properties - how distensible aorta is (based on shape and mechanical properties) determines:
- how hard LV has to work
diastolic pressure in aorta determines:
- coronary blood flow
- efficiency/dist of blood flow
*elastic component degenerates with age –> aorta stiffens –> systolic bp rises
[Acute Aortic Syndromes] - Aortic Coarctation
- Describe aortic coarctation and etiology/other associated conditions
- When does it cause problems?
- Pathophysiology
- Coarctation - constriction of aorta, esp isthmus
- occurs right as the ductus arteriosus joins the aorta (juxtaductal)
- congenital do not know etiology
- associated with other congenital heart defects –> bicuspid aortic valve, Turner syndrome (XO) - Does not cause problems in utero bc blood shunts from ductus arteriosus and down descending aorta, bypassing the constriction
- problem when baby is born and ductus closes - Pathophysiology - increased load caused by obstruction of the aorta leads to:
- increases afterload (increased pressure the heart has to work against) –> increased LV wall stress –> compensatory LV hypertrophy
- HTN (due to obstruction itself and also bc renal arteries are underperfused –> make renin to boost pressure)
- aortic collaterals –> rib notching classic finding seen later, in kids (not babies)
[Acute Aortic Syndromes] - Aortic Coarctation
1. Clinical presentation of aortic coarctation?
A. Infants
B. Older children and adults
2. Symptoms and signs
- Classic finding - notching on inferior surface of posterior ribs (chest X-ray)
A. Infants - differential cyanosis (bottom half of body), congestive heart failure (tachycardia, poor feeding)
B. Older children/adults –> systolic HTN in upper extremities, reduced lower extremity systolic BP (>20 mmHg)
- radial to femoral pulse delay - Symptoms and signs:
- majority of adults detected via incidental HTN
- one of the few murmurs that is heard on the back –> under left scapula
- bicuspid aortic valve in 30% adults (systolic murmur following ejection click)
[Acute Aortic Syndromes] - BAV
- Describe bicuspid aortic valve BAV and etiology/other associated conditions
- BAV clinical presentation
- Bicuspid aortic valve - 2 leaflets fuse during development –> bicuspid aortic stenosis
- M»F
- unknown developmental etiology: common, can be sporadic or familial (AD)
- 1/2 have dilated aortic root (need to be screened for this)–> can lead to aortic dissection, rupture
- structural alteration similar to that in CT disorders (Marfan, Ehlers-Danlos) *could be tied into etiology
- BAV associated with Turner syndrome, aortic coarctation - Clinical presentation: congenital
- aortic stenosis is most common, presentation at young age
- systolic ejection murmur/click that decreases with valsalva (↑ in intraabdominal pressure –> ↓ venous return to the heart –> ↓ blood flow through stenotic aorta)
Which 2 murmurs increase with valsalva maneuvers?
Valsalva –> ↑ in intraabdominal pressure –> ↓ venous return of the heart –> ↓ volume of heart
- Rapid standing –> also ↓ venous return (orthostatic hypotension)
- can reduce murmur by increasing preload (squatting) or afterload (handgrip)
- Mitral valve prolapse –> billowing of mitral leaflets happens sooner after S1 with lower blood flow –> mid-systolic click happens sooner
- Hypertrophic cardiomyopathy HCM –> exacerbates LV outflow tract obstruction bc ventricles come closer together with lower blood flow
[Acute Aortic Syndromes] - Aortic Dissection
- Describe aortic dissection pathophysiology
- Classification
- Etiology
- Aortic dissection:
- damage to aortic wall - combo of mechanical (HTN) and atherosclerosis –> degeneration of the media (necrosis and fibrosis)
- intimal layer tears (close to Aortic valve) –> high pressure allows blood to gain access to the underlying damaged media –>
- creates “false lumen” in which blood travels within media –>
- blood can propagate proximally (Towards heart) or distally (along aorta) and even encircle the aorta - Classification (Stanford)
- A - involves arch - treated surgically
- B - does NOT involve arch - treated medically - Etiology
- chronic arterial HTN most important risk factor
- smoking, cocaine use, eclampsia pregnancy, trauma
- genetic (Turner, CT disorders e.g Marfan)
- M»F
- 2x more common to begin in ascending (Vs descending) aorta
[Acute Aortic Syndromes] - Aortic Dissection
- Clinical presentation
- Compare/contrast presentation of chest pain in aortic dissection vs MI
- What are 3 things that can happen during catastrophic dissection?
- Clinical presentation - sudden, severe “tearing/ripping” chest pain - starts at maximal intensity (10/10) –> pain radiates to back/scapula –> Death
- HTN on presentation
- 1/2 have aortic regurgitation (blowing, decrescendo murmur heard best at 3rd L intercostal space)
- 1/3 have pulse deficits (can occlude branches of aorta) - MI - pain starts at lower level and gradually increases as myocardium becomes ischemic –> pain radiates to arm, shoulder, neck bilaterally
- Catastrophic dissection
A. False lumen ruptures –> patient dies (nothing you can do)
B. Occlusion of coronary ostia/opening –> MI
C. Proximal rupture into pericardium –> pericardial tamponade –> death
[Acute Aortic Syndromes] - Aortic Dissection
List high risk conditions, pain features, and physical findings indicative of aortic dissection
- High risk conditions - Marfan’s, family h/x of aortic disease, known aortic valve disease, recent aortic manipulation
- High risk pain features most important - chest, back, abdominal pain described as abrupt onset, severe (10/10) intensity, and “ripping or tearing”
- High risk physical findings - perfusion deficit (pulse deficit, systolic BP difference, focal neurological)
- new aortic regurgitation murmur (early diastolic decrescendo murmur, wide pulse pressure)
- hypotension
[Acute Aortic Syndromes] - Aortic aneurysmal disease
1. Define
2. Pathophysiology
A. Compare to pseudo-aneurysms
3. Etiology
A. compare to thoracic aneurysms
4. Clinical presentation incl symptoms of rupture
- Aortic aneurysm - localized/diffuse dilation of artery with diameter greater than 50% normal size (>3cm in abdominal aorta)
- most aortic aneurysms occur below renal arteries (infrarenal aorta), but can occur anywhere - Pathophys - ischemic injury of media (due to atherosclerosis), degradation of aortic medial connective tissue –> media broken down by proteases, poor quality vascular connective tissue –> expansion of aorta and thinning of wall
A. Pseudo-aneurysm - iatrogenic (post-surgical) resulting in hematoma (collection of blood in surrounding tissue) that remains in continuity with arterial lumen - Etiology - most abdominal aortic aneurysms AAA are acquired due to degenerative disease (HTN, smoking, atherosclerosis), acquired infection (Syphilis), inflammatory condition; M 65+ should be screened
A. Thoracic aortic aneurysm associated with family history / underlying genetic disorders e.g. Turner, CT disorders (Marfan, Ehlers-Danlos), Bicuspid aortic valve - Clinical presentation: usually asymptomatic before rupture
- typical finding is pulsatile abdominal mass
A. Symptoms of rupture - sudden onset abdominal OR back pain + hypotension = ruptured AAA
[Hyperlipidemia drugs] 1. HMG CoA reductase inhibitors (statins) A. MOA B. Effects on serum lipid concentration C. Adverse effects
- HMG CoA reductase inhibitors e.g. lovastatin (Mevacor), simvastatin (Zocor), atorvastatin (Lipitor) *first-line –> treatment and prevention of cardiovascular disease, decreased incidence of coronary events/death
A. MOA: Statins are competitive inhibitors of HMG CoA reductase (RLS in de novo cholesterol synthase from HMG CoA –> mevalonate)
- when cholesterol is down in the cell, SREBP (sterol regulatory element binding protein) is activated –> increases de novo biosynthesis (moot point bc of competitive inhibitor)
AND upregulates LDL receptors –> clears atherogenic lipoproteins from circulation via receptor mediated endocytosis
B. Serum lipid concentration
- decreases levels of TG, LDL
- little effect on HDL
C. Adverse effects
- side effects: myopathy (muscle aches, rhabdomyolysis), increased liver enzymes
- contraindicated for active/chronic liver disease, for pregnant women
- interactions: drugs that inhibit organic anion transporter e.g. cyclosporin –> higher plasma levels of statins
- red yeast rice is form of statin - natural but unregulated
[Hyperlipidemia drugs] 2. PCSK9 inhibitors (monoclonal antibodies) A. MOA B. Effects on serum lipid concentration C. Adverse effects
- PCSK9 Inhibitors e.g. evolocumab, alirocumab
A. MOA: inhibit PCSK9 - protein that binds to LDL receptors and delivers to lysosome for disposal –> higher levels of LDL receptors
B. Serum lipid concentration
- decreases levels of LDL
- little effect on TG (decrease), HDL (increase)
C. Adverse effects
- side effects - hypersensitivity rxns
- effective in reducing cardiovascular events, well tolerated but v expensive
[Hyperlipidemia drugs] 3. Cholesterol absorption inhibitors A. MOA B. Effects on serum lipid concentration C. Adverse effects
- Cholesterol absorption inhibitors e.g. ezetimibe (Zetia)
A. MOA: inhibits enterocyte brush border protein NPC1L1 - which inhibits uptake of dietary sterols –> leads to cholesterol uptake in small intestine –> decreased intestinal delivery of cholesterol to liver, increased LDL-R expression
B. Effects on serum lipid concentration
- decreased LDL
- no change in TGs
- slight increase in HDL
C. Adverse effects
- impaired hepatic function
- used with statins
[Hyperlipidemia drugs] 4. Bile acid sequestrants A. MOA B. Effects on serum lipid concentration C. Adverse effects
- Bile acid sequestrants (resins) e.g. cholestyramine, colestipol, colesevelam
A. MOA: positively charged plastics that bind negatively charged bile acids –> prevent their reabsorption –> bile acids secreted in stool –> increased hepatic bile acid synthesis from cholesterol –> liver [cholesterol] decreases
- LDL receptors increased
- but de novo cholesterol production also increased –> this homeostasis offsets LDL reduction
B. Effects on serum lipid concentration
- decrease in LDL
- slight increase in TGs
- slight increase in HDL
C. Adverse effects
- increase in hepatic TG synthesis –> contraindicated in patients with high TGs (>400 mg/dL)
- side effects from the plastics –> GI distress
- prevent interactions with other drugs by taking them at different times
[Hyperlipidemia drugs] 5. Niacin 6. Fibrates A. MOA B. Effects on serum lipid concentration C. Adverse effects
- Niacin
A. MOA: water soluble B3 vitamin that is incorporated into NAD
B. Effects: not been shown to have significant effects even in combo with statins but can decrease LDL, TG, and increase HDL
C. Adverse effects: causes niacin flush; hyperuricemia (gout), hyperglycemia, hepatotoxicity - Fibrates
A. MOA: Activate transcription factor PPARalpha - controls lipid metabolism
B. Effects: Reduces plasma TGs, little effect on LDL (may even increase)
C. Adverse effects: increase risk of myopathy in patients on statins
[Adrenergic agonists/antagonists]
- Where are the sympathetic neurons located?
- ID pre and post-synaptic SNS neurotransmitters
- Describe synthesis of the catecholamines
- Reuptake of NE
- Sympathetic neuron cell bodies in T1-L2 intermediolateral horns of spinal cord, leave through ventral horn –> why pain from viscera is so vague compared to pain from somatic nervous system
- Presynaptic - ACh
Postsynaptic - adrenergic (NE/E but mostly norepi) except ACh in sweat glands and D1 in renal vessels/ smooth muscle
3A. Cytoplasm: Tyrosine + (tyrosine hydroxylase RLS) –> Dopa –> Dopamine
B. Synaptic vesicles: Dopamine –> Norepinephrine
C. Adrenal medulla: Norepinephrine (acts as neurotransmitter) –> epinephrine (acts as hormone)
- NE/E are stored in chromaffin granules of adrenal
*When NE is released into synaptic space –> ATP is released as well
4A. reuptake into synaptic terminal (blocked by cocaine, TCAs)
B. Metabolism of NE to inactive metabolite (MAO in mitochondria, COMT in post-synaptic nerve)
C. diffusion away from nerve terminal
[Adrenergic agonists/antagonists] 1. Alpha1 adrenergic receptors A. MOA B. location C. physiologic effect
- Alpha1 adrenergic receptors
A. MOA: receptor coupled to Gq protein–> activates phospholipase C —> activates inositol triphosphate IP3-DAG cascade –> increased intracellular Ca2+
B. Located on postsynaptic membrane –> post junctional
C. Effects:
i. alpha1B (in vasculature) –> peripheral vasoconstriction and venoconstriction–> increases systolic and diastolic blood pressure
- increased SVR, MAP, and BP –> decreased HR / reflex bradycardia due to baroreceptor reflex
* minimal effects on heart
ii. alpha1A (in bladder sphincter) –> urethral sphincter and prostatic SMC contraction –> urinary retention
iii. mydriasis –> increased intraocular pressure when iris pulls back and obstructs canal of schlemm –> glaucoma
[Adrenergic agonists/antagonists] 2. Alpha2 adrenergic receptors A. MOA B. location C. physiologic effect
- Alpha2 adrenergic receptors
A. MOA: receptor coupled to Gi –> IP3-DAG cascade –> decrease cAMP levels –> inhibits release of neurotransmitters (NE and ACh)
B. Located on presynaptic membrane - nerve terminals of adrenergic and cholinergic neurons
C. Effects:
- autonomic modulation - inhibit NE and ACh release
- inhibit insulin release
- inhibit lipolysis
- decrease aqueous humor production –> decrease intraocular pressure
[Adrenergic agonists/antagonists] 3. Beta adrenergic receptors A. MOA B. location C. physiologic effect
- Beta adrenergic receptors - three types (1,2,3)
A. MOA: increase cAMP levels –> activates protein kinase A –> increase Ca2+ levels
- can be turned off by phophorylation
B. Location:
i. Beta1 - postsynaptic; heart, juxtaglomerular apparatus cells in nephron
ii. Beta2 - pre and postsynaptic; smooth muscle in periphery
iii. Beta3 - adipocytes
C. Effects:
i. Beta1
- increased Ca2+ –> increased inotropy (contractility)
- increased rate of conduction
- increased chronotropy (heart rate) by affecting funny current If; RMP more positive (cells more depolarized), fire more quickly bc close to threshold and reach threshold faster (slope to depolarization steeper)
- increased renin release in kidney nephrons
ii. Beta2
- increased bronchodilation, vasodilation, uterine relaxation
- increased insulin –> moves glucose and K+ into liver and skeletal muscle, respectively –> gluconeogenesis and hypokalemia
- decreased peripheral vascular resistance (opposite of alpha1)
- increased neurotransmitter release (if presynaptic)
- increased aqueous humor production
iii. Beta3
- lipolysis
[Adrenergic agonists/antagonists] Endogenous catecholamines: Epinephrine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Epinephrine
1. Key features: lower doses acts on beta, higher doses has alpha effects; B1=B2, alpha1=2 affinity
- Cardiovascular effects
- Beta1 - increased contractility, HR –> increased CO and systolic BP *increased myocardial 02 demand
- initially, B2 vasodilation in splanchnic beds –> decreased diastolic BP
- then, alpha1 contraction –>increased systolic and decreased diastolic BP –> mean arterial pressure MAP remains the same but pulse pressure increases - Clinical uses: #1 drug of choice for anaphylaxis (IV)
- cardiac arrest
- asthma (bronchospasm)
- local anesthetic
- open angle glaucoma - Toxicities - palpitations, HTN, tremor, anxiety
- contraindicated in hyperthyroidism and those on non-selective beta blockers
[Adrenergic agonists/antagonists] Endogenous catecholamines: Norepinephrine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Norepinephrine
- Key features: alpha1=2; Beta1»2
- at lower concentrations has high affinity for alpha
- at high concentrations, acts on Beta1 (heart) - Cardiovascular effects
- increased SVR (systemic vascular resistance)
- increased systolic and diastolic BP –> increased mean arterial pressure
- reflex drop in heart rate through baroreceptor response - Clinical uses: #1 drug of choice for hypotension in sepsis (IV) –> septic shock (type of distributive shock)
- Toxicities:
[Adrenergic agonists/antagonists] Endogenous catecholamines: Dopamine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Dopamine
1. Key features: effects are dose dependent
- Cardiovascular effects:
- (low dose) DA1 receptors in kidney –> increased renal perfusion –> diuresis
- (medium dose) Beta1 receptor in heart –> increase in contractility
- (high dose) Beta + alpha1 receptor –> increase in peripheral resistance –> increase contractility, HR, BP - Clinical uses: hypotension, low CO
- Toxicities: arrhythmia (Ventricular and supraventricular, widened QRS, angina)
[Adrenergic agonists/antagonists] Receptor-specific agonist: Phenylephrine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Phenylephrine
1. Key features: most specific for alpha1 agonist
- Cardiovascular effects: increased arterial vasoconstriction (skin, splanchnic vessels, skeletal muscles) –> increase BP
- decreased HR due to baroreceptor reflex (reflex bradycardia) - Clinical uses: #2 drug for hypotension (IV) if you cannot use NE
- rhinitis (vasoconstricts to treat nasal congestion)
- mydriasis - Toxicities: black box warning bc it is has active metabolite in liver/tissues –> can cause HTN when supine
[Adrenergic agonists/antagonists] Receptor-specific agonist: Clonidine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Clonidine
1. Key features: alpha2 agonist at presynaptic receptors in medullary brainstem; imadazoline compound; oral and transdermal
- Cardiovascular effects: decrease central SNS outflow –> decrease HR, decrease SVR, increase capacitance
- Clinical uses:
- resistant and urgent forms of HTN
- mgmt of Tourette’s, ADHD
- also used for hot flashes, addiction withdrawal - Toxicities: dry mouth, sedation, depression, rebound HTN
* other drugs in same class: guanabenz, guanfacine (not used)
[Adrenergic agonists/antagonists] Receptor-specific agonist: Isoproterenol 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Isoproterenol
1. Key features: IV only; acts non-selectively at beta receptors; beta1=2 agonist
- Cardiovascular effects:
- Beta1 - increase HR (chronotropy), contractility (intotropy), conduction velocity
- Beta2 - decrease peripheral vascular resistance (decreased afterload on the heart) –> decreased diastolic BP - Clinical uses: stokes-adams attack (syncope due to absent pulse), cardiac arrest, heart block
- Toxicities: tachycardia, HTN, dysrhythmia
* not really used clinically
[Adrenergic agonists/antagonists] Receptor-specific agonist: Dobutamine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Dobutamine
1. Key features: beta1 selective but (-) isomer has some alpha1 effects
- Cardiovascular effects: increased contractility»_space; chronotropic effect
- alpha1 action maintains peripheral resistance (makes it a better drug than isoproterenol) - Clinical uses: #1 drug for cardiogenic shock with maintained BP
- add to NE in septic shock with low CO
- stress test - Toxicities: tachyarrhythmia, PVCs, HTN
[Adrenergic agonists/antagonists] Phenoxybenzamine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Phenoxybenzamine
1. Key features: non-selective alpha antagonist –> blocks both alpha1 and 2 but 1»2; irreversible (blockade lasts 2 days), oral administration only
- Cardiovascular effects: blocks reuptake at presynaptic terminals –> blocks catecholamine-mediated vasoconstriction –> decrease TPR
- metabolically neutral - no effects on glucose, lipids, GFR, ions, etc - Clinical uses: oral
- pheochromocytoma (adrenal medulla tumor with excessive production of catecholamines NE/E) –> causes paroxysmal hypertension
* only used to premedicate patients with this condition before surgery; start with alpha blocker, then beta - or they could suffer a stroke in the OR - Toxicities: orthostatic hypotension, reflex tachycardia, nasal stuffiness, fatigue, nausea
[Adrenergic agonists/antagonists] Phentolamine 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Phentolamine
1. Key features: non-selective alpha antagonist; alpha1=2; reversible (lasts 4 hours); IV or IM only
- Cardiovascular effects: blocks peripheral resistance, causes cardiac stimulation
- Clinical uses: NE extravasation (when IV with NE leaks into the tissue and causes vasoconstriction and necrosis); pheochromocytoma, treating patients on MAO inhibitors who eat tyramine-containing foods (wine, cheese)
- Toxicities: severe tachycardia, arrhythmias, myocardial ischemia
[Adrenergic agonists/antagonists] Prazosin 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Prazosin
- Key features: highly alpha1 selective (1000x»_space; than alpha2) antagonist
- other drugs are terazosin, doxazosin, tamulosin - Cardiovascular effects: post-junctional antagonist
- relaxes arterial and venous smooth muscle –> increases venous capacitance –> vasoilation, decreased TPR
- relaxes smooth muscle in prostate
- metabolically neutral - no effect on glucose, GFR, etc - Clinical uses: benign prostatic hyperplasia BPH
- also HTN, but not first line therapy (which is diuretics)
- used in older men with HTN and BPH - Toxicities: postural hypotension, dizziness, headache, drowsiness, ejaculation problems
[Adrenergic agonists/antagonists] Beta blockers 1. Key features 2. Cardiovascular effects 3. Clinical uses 4. Toxicities
Beta blockers
- Key features: metabolized extensively –> limited bioavailability with oral administration
- Beta1 - in SA node (increase HR), cardiac muscle (contractility, SV), and renal juxtaglomerular cells (renin release)
- Beta2 - on VSM cells (vasodilitation) - Effects: immediate CO ↓ and TPR ↑
- only has BP lowering effect when BP is high
- negative chronotrope (slows HR)
- negative inotrope (decreases contractility)–> lowers CO, workload, V02
- can increase PVR initially, but normalizes long-term
- bronchoconstriction, even if B1 selective
- metabolic/endocrine: block lipolysis –> increased VLDL, decreased HDL; blocks glucose mobilization
- eye: decreases aqueous humor production –> reduce intraocular pressure in the eye - Clinical uses
- propranolol - acute STEMI (decreases myocardial 02 consumption)
- metoprolol in symptomatic heart failure
- hyperthyroidism, glaucoma, migraine
- no longer first line for HTN - - Toxicities
- drug rebound - can precipitate acute MI on sudden withdrawal
- CHF exacerbation - in patients with acute decompensated heart failure
- bradyarrhythmia - in patients with AV conduction defect
- bronchoconstriction - contraindicated with severe obstructive disease
- weight gain, lipid metabolism, worsened glycemic control in DM II
[Adrenergic agonists/antagonists] Beta blockers 1. List non-selective antagonists 2. Beta1 selective antagonists 3. Non-selective beta blockers + alpha blocking activity
- List non-selective antagonists:
- propranolol - prototypical
- pindolol - partial agonist
- nadolol - LONG duration of action
- timolol - ophthalmic, topical tx for glaucoma - Beta1 selective antagonists - used in patients with asthma, COPD, DM
ABEAM
Acebutolol - partial agonist
Betaxolol
Esmolol - parenteral, SHORT duration (10 min 1/2 life)
Atenelol - prototypicals
Metoprolol - prototypicals
- nebivolol - most highly selective beta1; vasodilation via NO release; does not affect lipid/glycemic control - Non-selective beta blockers + alpha blocking activity
- carvedilol - used in CHF and HTN; best choice with nebivolol in diabetic patients
- labetolol - treats HTN in pregnancy
