Systems- Cardiovascular Flashcards
Cardiac output equations
Q= change in P/R
Q= MAP(-CVP)/TPR
Poiseulle’s law
R= 8 x viscosity x length of tube / pi x radius^4
Overall Q
MAP / 8vL/pi(r^4)
Starling equation
Net volume flow= alpha[(hydrostatic pressure difference) - delta(osmotic difference)]
Hypokalaemia
From low dietary K+ or starvation
-> diarrhoea, excess sweating and urinary excretion
ST depression
Extra U wave due to prolonged repolarisation of purkinje fibres
Atrial arrythmias
Ventricular tachycardia or fibrillation
Sinus tachycardia
Rate more than 100bpm Otherwise normal (regular narrow QRS)
Ectopic beats
Missed beats and extra thumps
Felt most at rest, where there is increased awareness
Supraventricular tachycardia
Rate more than 100bpm
No P wave, hidden in QRS
Regular narrow QRS
AVN reentry via slow and fast pathways
Treat with adenosine, valsalver manouver, ablation to cauterise slow pathway
Clearly defined episodes of around 7 minutes
Atrial fibrillation
Waves of reentry to atria
Risk of stroke
No P waves, no organised depolarisation
Fluttery, weak and strong beats
Atrial flutter
Rate variable- atria around 300bpm, ventricles 150bpm
Regular narrow QRS
Sawtooth atrial ECG
Clockwise impulse wave around right atrium
Ventricular tachycardia
Rate more than 120bpm
Regular broad QRS
P waves variable
Wolff-Parkinson-White syndrome
Conduction from atria to ventricles before AVN
In combination with atrial fibrillation can cause death
Short PR interval
Slurred upstroke
Sinus bradycardia
Rate less than 60bpm Otherwise normal (regular narrow QRS)
Junctional bradycardia
Rate less than 60bpm
No P wave
Regular narrow QRS
Vasovagal syndrome
Vasodilation
Triggered by PPP- posture, prodrome, precipitant, then syncope
Tested in tilt test
Arrythmic syncope
Random, any posture
Infrequent- sudden onset and fast recovery
Sinoatrial disease
Malfunction of SAN
Often associated with atrial tachycardias- dangerous as cant slow tachycardia to normal pacemaker
1st degree heart block
Rate variable
Regular narrow QRS and P wave
Slow PR interval
= AVN block
2nd degree heart block
Mobitz- Irregular narrow QRS, not 1:1 with P
Wenckebach- Irregular narrow QRS, not 1:1 with P
- Increasing PR interval, then dropped beat
Complete heart block
Regular broad QRS
No conduction though purkinje fibres
No relation between P and QRS
Needs immediate temporary pacing
Inotropy
Force of contractility
Chronotropy
Rate of contraction
Dromotropy
Rate of electrical conduction
Statins
eg Lovarstatin, Atarvastatin
Inhibit enzyme 3-hydroxy-3-glutyl coA reductase which is the rate controlling enzyme of mevalonate pathway producing cholesterol
Used to prevent atherosclerosis
Causes- decreased liver cholesterol synthesis
- increased VLDL and LDL receptor expression, so decreased LDL in blood
Fibrates
Used to prevent atherosclerosis
Ampipathic carboxylic acids, agonists of peroxisome proliferator activated receptor alpha (PPAR-alpha)
-> increased beta oxidation in liver, decreased hepatic triglyceride excretion, increased VLDL clearance by lipoprotein lipase
Bile acid binding agents
Used to prevent atherosclerosis
Increase loss of bile acid via gut, so decreased liver cholesterol, increased LDL receptor expression, less LDL in blood
Nitrates
Used to control angina
Increased NO, stimulates guanylate cyclase, activates cGMP-dependent protein kinase, activates myosin light chain phosphorylation, vasodilation
Venous vasodilation-> reduced preload
Arterial vasodilation-> reduced afterload
Side effects- headache
- flushing
- palpitations
- tolerance
- interactions with impotence drugs (viagra) leading to hypotensive crisis
Beta blockers
Used to control angina
eg Propanolol, Atenolol, Carvedilol
1st line treatment for chronic stable angina
Reduces myocardial oxygen demand by blocking beta 1 receptors on the heart, slowing heart rate and contractility
Fewer side effects
Calcium channel blockers
Used to control angina and treat hypertension
Less Ca entry to smooth muscle, vasodilation, less heart contraction, less myocardial oxygen demand
Side effects- peripheral vasodilation-> dizziness, headache, erythema, peripheral oedema
- constipation
- HR changes
eg Dihydropiridines (Nifedipine), Phenylalkylamines (Verapamil), Benzothiazepine (Diltiazem)
Aspirin
Antiplatelet
Used to treat post MI
NSAID (non steroidal anti inflammatory)
Metabolized to salicylate
Used in low dose long term to prevent MI, strokes, blood clots
Irreversibly inactivates COX in both platelets (making thromboxane A2, increasing clotting) and endothelial cells (making prostaglandins PGI2, inhibiting clotting)
Endothelial cells have nucleus, so can make more prostaglandins almost immediately, platelets can’t make more thromboxane A2 for 7-10 days so overall inhibits platelet aggregation
Low dose of 180mg/day effective in preventing ministroke
335mg/day decreases risk of MI
More than 1000mg/day has no effect, as inhibits endothelial COX also, so cancelling out antiplatelet effect
Clopidogrel
Antiplatelet
Prodrug that irreversibly blocks ADP receptor on platelet cell membranes
Blocks activation of glycoprotein IIb/IIIa pathway, so prevents amplification of clot formation
Side effects (few)
Decreases risk of stroke, MI, vascular death
Ranolazine
Used post MI where there is high risk of electrical disturbances in the heart
Blocks late Na entry, increases QT interval
Nitric Oxide
Produced by endothelial cells Causes VSM relaxation (vasodilation), modulates cardiac contraction, inhibits platelet aggregation =EDRF (endothelial derived relaxing factor) ACh-> increase Ca conc in endothelial cell -> endothelial nitric oxide synthase produces NO-> NO to guanylate cyclase of smooth muscle cell-> GTP to cGMP to PKG-> decreased Ca levels-> relaxation Can be removed by cGMP phosphodiesterase, but NO has short half life and would degrade quickly anyway
Mean arterial pressure
MAP= 1/3 pulse pressure + diastolic pressure
MAP= (CO x TPR) + CVP
Thiazides
eg Hydrochlorothiazide, Bendroflumethiazide
Treat hypertension via blocking the na/cl symporter in DCT
Mild, so limited use
Also direct vasodilator action, so gives 2 beneficial effects
Calcium channel blockers
eg Nifedipine
To treat hypertension
Vasodilators, reduce peripheral resistance and reduce filling pressures
ACE inhibitors
eg Captopril and Enlapril
To treat hypertension
Inhibits angiotensin I->II
1) rapid phase due to direct anti ang II effect
2) slow phase due to blood volume effect and control of thirst
Ang II receptor blockers
Eg Losartan
To treat hypertension
Limits blood volume expansion so less water retention, less thirst
Alpha 1 adrenoreceptor blockers
Eg Prazosin, (Doxazosin in emergencies)
To treat hypertension
Block constriction of VSM (so vasodilate) by antagonising noradrenaline
K+ channel activators
Eg Minoxidil, Pinacidil
To treat hypertension
Inhibits calcium entry into cell by blocking k exit
Alpha methyl dopa
To treat hypertension
Prodrug, converted to methyl noradrenaline in SNS
Displaces NA but is not metabolised by MAO
Unselective, so only last resort
Ganglion blockers
Eg Guanadrel
In uptake 1, Guanadrel substitutes for NA in secretory granules
So decreases sympathetic effects
Many side effects, so last resort, inhibits all sympathetic ganglia
Quinidine
Class 1a antiarrhythmic
Moderate Na channel blocker
Prolongs action potential duration, reduces upstroke
Reduces Na entry to cell
Binds to Na channel (slow)
Slows phase 4 depolarisation, suppresses propagation of automaticity
Lignocaine
Class 1b antiarrhythmic
Weak Na channel blocker
Decreases action potential disrupt, reduces upstroke
Suppressed automaticity by prolonging the refractory period, decreasing conduction, decreasing Na influx (so Ca influx)
For treatment during and immediately after MI, emergencies only
Flecainide
Class 1c antiarrhythmic
Strong Na channel blocker
Suppresses automaticity
Increases refractory period
Useful in WPW syndrome, CPVT, recurrent tachyarrhythmias
For post MI to decrease cardiac contractility
Atenolol
Class II antiarrhythmic Beta blockers Increase action potential duration Increases refractory period Decrease SAN/AVN conduction Haemodynamic depressant For supra ventricular tachycardia
Amiodrorone
Class III antiarrhythmic K channel blocker Increases action potential duration Increase refractory period For WPW syndrome, ventricular tachycardias, atrial fibrillation
Diltiazem
Class IV antiarrhythmic
Ca channel blockers
Difficult to target cardiac not vascular Ca channels
Blocks AVN so good for supra ventricular tachyarrhythmias
Prevent recurrence of paroxysmal supra ventricular tachycardia
Reduce ventricular rate where atrial fibrillation
Magnesium
Used as antiarrhythmic Reduces Ca entry through sarcolemma Binds ATP and regulates metabolic processes Depleted in ischaemic cells Valuable in ventricular arrhythmias
Occasionally genetics- pro arrhythmic
Adenosine
Antiarrhythmic agent
For supra ventricular tachycardias
Enhances k current in atrial tissues
Digitoxin
Long duration
Slow onset
Lipophilic- good absorption, strong binding to serum proteins
Act at Na/K ATPase (3 Na out 2 K in) on cardiac glycosides binding sites opposite ATP binding sites on alpha subunit
So decrease Na in cell, some depolarization
Increase Ca in cell via Na/Ca exchange
Increase Ca in cell via sarcoplasmic reticulum pump release
Increase contraction strength (increase force and excitability, decrease A-V conduction and rate)
Not first line but still potent, careful titration needed, used when atrial flutter or fibrillation is present in HF
Dobutamine
Receptor sympathomimetics
For reversible HF
Beta 1 selective
Given intravenously
Milrinone
Transduction sympathomimetics
Last line treatment for HF
Increases cAMP by inhibiting cAMP phosphodiesterase, so increasing PKA activity
Glyceryl trinitrate (GTN)
Nitrate For acute hospital cases of HF Metabolized to release NO Decreases preload and afterload Decreased venous return, so increased CO when decompensated
Lowering free cholesterol by decreasing HMG CoA reductase
Diet- less saturated fats, increased polyunsaturated fats
Drugs- simvastatin, atorvastatin
1st line (50% decrease in cholesterol possible)
Lower free cholesterol by decreasing intestinal uptake of chylomicron remnants
Diet- plant stanols, benecol
Drugs- ezetimibe
2nd line (10% decrease in cholesterol possible)
Lowering free cholesterol by increasing bile acid excretion
Diet- increase fibre intake Drugs- cholestyramine 3rd line (bad GI side effects)
Furosenide
Loop agent diuretic Acts at ascending limb of loop of Henle Inhibits Na/K/Cl transporter Powerful Useful for pulmonary and refractory oedema and kidney failure
Spironolactone
K sparing diuretic Acts at convuluted tubule Antagonises aldosterone Weak Useful for controlling K loss (so used with loop agents)
Warfarin
Inhibits carboxylation of factors II, VII, IX, X so tissue factors cannot localise to platelets
Oral administration, long term therapy
Slow onset (12+hours), 4-5 day duration
Strongly binds to plasma proteins
Metabolized in liver
Measure prothrombin time (PT) to measure action (clotting time of plasma from patient blood sample following addition of calcium, expressed as ratio, gives INR value, low value is best)
Potentiated by
- drugs displacing it from plasma proteins eg aspirin, so increases its concentration in bloodstream
-drugs interfering with liver function, slowing its breakdown
-drugs which interfere with platelet function
-liver disease
-decreased vitamin k availability
Decreased by
- drugs which induce metabolizing enzymes
-promoted clotting factor synthesis (vitamin k)
-reduced warfarin absorption
Side effects- haemmorhage (stop warfarin until INR below 5.0, give vitamin K)
- tertogenic, affecting foetal development, so not used in pregnancy
Heparin
Binds antithrombin III, so removes factors IIa and Xa from the bloodstream
LMW heparin inhibits only Xa so less potent
In vivo administration, or injected IV or SC
Complex pharmacokinetics due to plasma protein binding
Initially rapidly removed as it binds to endothelial/macrophage cells
Slower subsequent removal by renal excretion, so give large initial dose then match dosage with renal excretion
lMW has immediate IV effect as doesn’t bind to plasma protein
Prasugrel
Irreversible ADP receptor antagonist
Antiplatelet
Fast onset
Very effective, so higher risk of bleeding
Ticlopidine
Irreversible ADP receptor antagonist
Antiplatelet
Slow onset of 3-7 days
Decreases stroke risk
Ticagrelor
Reversible ADP receptor antagonist
Antiplatelet
Because it is reversible, can be an asset in some clinical scenarios
Abciximab
IIb/IIIa receptor antagonist
Antiplatelet
Antibody fragment directed against receptor
Used IV in high risk coronary angioplasty with heparin and aspirin
Only single administration, as will become immune
Tirofiban
IIb/IIIa receptor antagonist
Antiplatelet
Cyclic peptide resembling IIb/IIIa ligands
IV administration
Epoprostenol
Prostaglandin agonist
Antiplatelet
IV administration
For patients undergoing haemodialysis where they cannot have heparin
Dipyridamine
Phosphodiesterase inhibitor
Antiplatelet
Increases platelet cAMP levels
Streptokinase
Fibrinolytic agent
From streptococci bacteria
Blocked by antibodies after 4 days so is then ineffective, limit use to 1x per year
Recombinant tPA
Fibrinolytic agent
Clot specific, more active at fibrin bound plasminogen
Alteplase- short half life
Reteplase- long half life
Contraindications, side effects and uses of Fibrinolytic agents (tPA, SK, UK)
Contraindications
- Absolute - active/recent internal bleeding
- recent cerebrovascular accident
- invasive procedures where haemostasis needed
- Relative - pregancy
- cardiopulmonary resuscitation
- trauma
- bacterial endocarditis
Side effects- GI haemmorhage
- allergic reactions
- can generate kinins-> hypotension
Used in acute MI, acute thrombotic stroke, clearing thrombosed shunts, acute arterial thromboembolism
Antifibrinolytic drugs
Tranexamic acid- inhibits plasminogen activation, used in high bleeding risk
Aprotinin- proteolytic enzyme inhibitor of plasmin, used in high bleeding risk during or after open heart surgery
Drugs to treat venous thrombosis
Heparin or Warfarin
To reduce effectiveness of clotting cascade
Reduce formation of fibrin
Drugs to treat arterial thrombosis
Aspirin, Clopidogrel, Abciximab
Reduce platelet activation
Used in acute MI, high risk MI, after coronary bypass, unstable coronary syndromes, after coronary artery angioplasty, thrombotic stroke
Drugs to treat life threatening thrombosis
Alteplase
Fibrinolytic drug, recombinant tPA
Activates plasminogen, increasing fibrin breakdown
Right ventricular failure signs/symptoms
Raised CVP (JVP)
Hepatomegaly as congested liver
Peripheral oedema
Parasternal heave (ventricular enlargement)
Murmur of tricuspid regurgitation
Nocturia as fluid from legs returns to circulation
GI organs congested with blood, so abdominal discomfort
Left ventricular failure signs/symptoms
Symptoms- dyspnoea (breathlessness) as pulmonary venous congestion
- orthopnoea when lying flat, blood from limbs to lungs
- fatigue as reduced perfusion of skeletal muscle
Signs
- cachexia (frail appearance)
- diaphoresis (excessive sweating)
- cool peripheries
- tachycardia
- tachypnoea
- murmur of mitral regurgitation
- crepitations in lungs (congested)
- cardiac wheeze
ANP
Atrial natriuretic peptide
Released by atria in response to stretch
Causes more urine excretion to lower blood pressure
Preload
The load on a myocyte prior to contraction, =filling pressures
Afterload
The load against which the heart has to work to eject blood
Starlings law of the heart
The energy of contraction of a cardiac muscle fibre is proportional to the fibre length at rest
Adrenaline in high concentration
Alpha 1 receptors
Vasoconstriction
Adrenaline in low concentration
Beta 2 receptors
Vasodilation
Investigations- Exercise treadmill test
Cheap Available in clinic Instant result Insight to exercise capacity but- Low sensitivity and specificity
Investigations- CT Calcium scoring
Good for ruling out atherosclerosis, not good at ruling in
(Lights up any calcification)
Used in low likelihood of CAD
Investigations- Myocardial perfusion scan
(Radionuclide injected, viable tissue takes up, infarcted does not) Good information given Lesion specific but- High radiation dose - False positives and negatives given - Time consuming If intermediate likelihood of CAD
Investigations- Stress echo
(Stressed via exercise or dobutamine, then look at LV function with ultrasound to see contraction)
No radiation
Equipment readily available
but- Only short time frame available to get images in (90s)
- Not all views of heart possible
- Consultant led
If intermediate likelihood of CAD
Investigations- Cardiac MRI
Compare in rest vs stress Give adenosine for maximal dilation of vessels and then can watch blood travel through heart Very good definition No radiation If intermediate likelihood of CAD
Investigations- Coronary angiography
BEST
Pass catheter to heart, squirt dye and watch passage of blood through
but- Invasive, risk of MI and death, damage to artery
Treating CAD
Lifestyle: Weight loss Diet change (even if slim) Hypertension/cholesterol/diabetes control Smoking cessation ESSENTIAL
Medication: Aspirin Statins B blockers/ Ca channel blockers Nitrates (symptomatic relief)
Coronary angioplasty
Coronary artery bypass grafting
Pathophysiology of heart failure
Inadequate tissue perfusion and volume overload
-> Enlarged ventricles, spherical shape, reduced efficiency
Drugs to treat heart failure
Diuretics Vasodilators (nitrates) ACE inhibitors Angiotensin II receptor antagonists Positive ionotropic drugs- cardiac glycosides and sympathomimetics
Myogenic autoregulation
Bayliss effect
High bp distends arteries, which respond by contracting (negative feedback)
Stretch-activated ion channels open, depolarisation, voltage-gated ion channels open, Ca enters, VSM contraction
Minimises capillary flow fluctuations and irregular tissue exchange
Autoregulation
Blood flow remains near constant over a range of pressures by regulating local resistance from signals from blood vessels or surrounding tissue
Metabolic autoregulation- active and reactive hyperaemia
Local vasodilation caused by CO2, acidosis, lactate, adenosine, K+, hypoxia
Active: increased metabolic activity, decreased O2, increased metabolites, vasodilation, increased flow
Reactive: flow occlusion, accumulation of vasodilating metabolites, rapid and transient increase in flow
Metabolic autoregulation- autocoids
Vasoactive chemicals,
eg histamine, bradykinin cause vasodilation
endothelin, serotonin cause vasoconstriction
Produced, released and acting locally
For inflammation, trauma and clotting
Metabolic autoregulation- eicosanoids
Mediate inflammatory responses
Cause vasodilation
eg Prostaglandins, thromboxane
Endothelial regulation causing vasodilation
Shear stress, ACh, histamine, bradykinin, ATP
Causes endothelial production of EDRF (endothelial derived reacting factor), NO
Stimulates guanylate cyclase in VSM, relaxation
Endothelial regulation causing vasoconstriction
Circulating factors eg ADH
Cause release of endothelin-1
Opposite effects to NO, increased SR release of Ca, vasoconstriction
Nitric oxide synthase (NOS)
Only active as dimer
Presence of BH4 necessary for action
Activated by calmodulin and reversible phosphorylation
3 isoforms- eNOS (endothelial) and nNOS (neuronal) are Ca dependant, synthesise NO basally upon stimulation
-iNOS (inducible) is Ca independant, for inflammatory response induced by ischaemia- reperfusion, HF, ageing, septicaemia
Uncoupled in oxidative stress (diabetes, hypertension, atherosclerosis, chronic smoking), where can’t use arginine as a substrate so uses O2 instead which is converted to superoxide
Nitric Oxide effects
Inhibits platelet adherence Inhibits leukocyte chemotaxis Inhibits smooth muscle cell proliferation and migration Promotes endothelial regrowth Vasorelaxation
When combined with superoxide, makes ONOO- and No2 which damage mitochondria, break DNA leading to cell death
RAAS effects
ADH secretion from posterior pituitary, so H2O absorption from collecting duct
Increased sympathetic activity
Aldosterone secretion from adrenal cortex, so increased tubular Na/Cl reabsorption and K excretion, H2O retention
Arteriolar vasoconstriction, so raise in BP
Overall water and salt retention to increase blood volume, inhibits renin release by Kidney for angiotensin to 1, negative feedback loop
Haemostasis
Endothelium release inhibiting factors NO and PGI2, these check endothelium for damage
Von Willebrand factor links collagen on damaged vessels to platelets
Activated platelets release ADP and thromboxane A2, amplification
ADP binds to G protein coupled ADP receptor P2Y12
Activation of integrin IIa/IIIb and fibrin binding leading to platelet aggregation
Anti-clotting cascade
-Antithrombin III
-Proteins C and S
-Thrombomodulin
Cleave Va and VIIIa so they are INactivated, cannot be reactivated
-Lipoprotein tissue factor pathway inhibitor
Endocytosis and degradation of Xa and VIIa so no prothrombin to thrombin
Intact endothelium discourage thrombosis by…
Express sulphated mucopolysaccharides which activate antithrombotic enzymes
Express tissue plasminogen activator, activating plasminogen, active destruction of thrombus
Synthesise prostacylin, which dilates vessels and disaggregates platelets
Platelet Derived Growth Factor
Triggers SMCs to change in atherosclerosis, become more like fibroblasts and migrate up to become fibrous cap
