Revision Cards Flashcards
What is personalised medicine?
PM aims to customise healthcare with decisions and treatments tailored to each individual patient. Particularly important in older people with multi-morbidity.
Pharmacogenomics is an important part of PM: how a person’s genome influences their response to medications e.g SNP in Cpt metabolizing enzymes
How is PM emerging and what are the benefits?
Increased importance in PM since 2003 when the human genome project was completed e.g increase from 4 to 104 drugs with pharmacogenetics on the label
PM can reduce trial and error prescribing, avoid adverse reactions, increase patient compliance, reveal additional uses and limit costs of healthcare.
What are some recent examples of how PM is being implemented into treatment?
- Warfarin: Anticoagulant drug that thins blood. Used to treat deep vein thrombosis or pulmonary embolism. Genome affects your ability to metabolise drug, thereby affecting the concentration in your blood.
- Familial Hypercholesterolemia: Inherited form of increased lipids in the blood. Mutation leading to a defect in LDL protein receptor. Increased risk of cardiovascular disease.
- Allomap gene test: Test blood for a number of gene which will give an indication for the likelihood of rejection following a heart transplant.
What is Clopidogrel?
One of the first examples of a pharmcogenomic approach. Inhibits plateleys from sticking together, to prevent against a clot.
CYP2C19 enzyme family metabolise Clopidogrel into its active form. If there is a mutation in the enzyme, poor metabolisers - resistant to drug.
Not routinely screened for genetics but point-of-care testing for platelet stickiness can be carried out.
What is inter-individual variation?
Variations in concentrations of the drug at the site of action or different responses to the same concentration of drug.
- Pharmacokinetic variation: the drug concentration changes in relation to different parts of the body affecting the dose and drug response e.g. absorption and excretion
- Pharmacodynamic variation: individualised response to drugs, drugs like anti-hypertensives, anticoagulants are adjusted by measuring physiological endpoints at the bedside.
Why do you need to be careful looking at graphs showing effects of a drug?
Variation lies behind the bars of the graph, there are often extreme outliers which may be important. Note the number of individuals involved and specific factors like their age which may affect the result. Ideally look at the individual points of data themselves to identify significant difference.
What are the main causes of variability in drug responses?
- Age: organs aren’t as well develop in newborns, and body composition and polypharmary affects older people
- Ethnicity: e.g SNP in chinese affect ability to metabolise ethanol
- Genetics/Genomics
- Immunological factors: interaction with antibodies (treatment for RA or breast cancer)
- Concomitant Disease: in liver/kidney affects secretion/drug conc. Pregnancy.
- Drug interactions
How does age affect drug action?
Drug elimination is less efficient in newborns and older people. Glomerular filtration rate is 20% of the adult value.
Digoxin half life: 100hr in neonate, 40hr in adult, 80hr in elderly
Drug metabolising enzymes altered in newborns.
Body composition changes with age but varies between people.
How does ethnicity affect drug action?
Variation in genetics between ethnicities, possibly also environmental factors like diet.
Some drugs are known to have an ethnicity complication e.g. Hydralazine has increase halflife in African Americans
Some ethnicities receive increased benefit over normal responses, others have disbenefits.
Genome testing would be more useful than asking about ethnicity.
How does genetics affect drug action?
Mutations (heritable changes in DNA) causing slow/fast acetylators. e.g. 50% of British are deficient in N-acetyltransferase
Polymorphism (alternative sequence at loci within the DNA strand/allele). C-T is the most common. e.g. Inherited thrombophilia is caused by a SNP in factor V Leiden (coagulation factor). Increase in clotting.
How do concomitant diseases affect drug action?
Diseases affecting the liver and kidney can cause prolonged or intense drug effects.
Some diseases cause gastric stasis (delayed gastric emptying).
Some diseases can affect receptors e.g. Familial hypercholesterolemia is an inherited conditionleading to lack of function of LDL receptors. Statins are ineffective.
How do interactions with other drugs affect specific drug action?
Can refer to other drugs or chemical such as grapefruit juice or herbal remedies.
There are some predictable reactions that we know:
e.g. Diuretics used to treat heart failure will act to decrease fluid but will also lower plasma K+ and predispose to digoxin toxicity
e.g. Sildenafil (vasodilator) mechanism of action potentiates organic nitrates and the combination can lead to sever hypotension.
What is an example of a gene test done to determine drug dosage?
Gene test for alleles of CYP2C9 and VKORC are tested before patient is given Warfarin. Drug used to thin blood. CYP2C9 metabolises Warfarin. Balance needed to avoid excess bleeding and thrombosis. There are 3 polymorphisms in two targets which will affect efficacy.
CYPC9 can be any combination of *1, *2, *3.
VKORC can be GG, AG, or AA (where GG is the WT allele).
3/3 and AA are rarer genotypes that require specifically low doses of Warfarin (0.5-2mg)
What is the careful balance that Warfarin seeks to achieve?
Keep the patient’s International Normalised Ratio (INR), a measure of blood coagulation, within a target range, usually between 2 and 3. If the INR is too low, the risk of blood clotting remains, if the INR is too high, there is a new risk of bleeding.
What are the phases of the cardiac action potentials?
Membrane potential at rest: -70mV
Phase 0: Rapid depolarisation caused by a rapid sodium influx from voltage-dependent Na channels. All or nothing response (must reach critical point).
Phase 1: Partial repolarisation due to outside current (small downstream). Rapid sodium influx deactivation.
Phase 2: Plateau maintained by the slower longer calcium influx. Initial outward fall in K also helps maintain plateau.
Phase 3: Repolarisation to return to membrane potential at rest. Deactivation of inward calcium current and increase of outward potassium current.
Phase 4: Pacemaker potential. Gradual decrease of K, gradual increase in Na/Ca (gradual depolarisation in diastole) but not reaching critical point). Only found in nodal and conducting tissue.
What is the cardiac conduction tissue?
Specialised tissue known as nodes. Between the SAN and AVN there are atria and ventricles. From SAN electrical signal will spread through atrial muscle and defined pathways like Bachmann’s bundle.
Reaches AVN after a delay which allows Atria to contract before ventricles. On reaching AVN it spreads through bundle of His and reaches Purkinje fibres causing contraction of the ventricles.
What are the electrophysiological features of cardiac tissue?
-Action potentials look slightly different for SAN, Atria, AVN, purkinje fibres and ventricles.
-Pacemaker potential (gradual depolarisation) only occurs in SAN, AVN and purkinje fibres.
-There is an absence of a fast current Na in SAN and AVN, instead they are controlled by slow Ca.
-There is a long action potential (plateau) and refractory period in Purkinje fibres and ventricles to prevent the tissue becoming immediately depolarised again and contracting straight away.
Influx of calcium to maintain plateau.
What are the mechanisms of arrhythmia?
Abnormal impulse generation (starts somewhere it shouldn’t)
-Triggered activity (delayed after depolarisation)
-Increased automaticity (ectopic activity)
Abnormal impulse propagation (travels where it shouldn’t)
-Re-entry (circus rhythm)
-Heart block (atrioventricular block)
What is triggered activity?
Triggered activity is the presence of abnormal action potentials are triggered by a preceding action potential, and can result in either atrial or ventricular tachycardia. It is due to calcium overload in the cell. Occur ‘after-depolarisation’. In late phase 3 or early phase 4 when the action potential is nearly or fully repolarized. The triggered impulse can lead to a series of rapid depolarizations.
What is Automaticity?
Automaticity occurs when abnormal cardiac cells in the SAN cause inappropriate firing of action potentials. Pacemaker activity is abnormal or they fire spontaneously creating premature heart beats.
What is re-entry?
Abnormal heart tissue means conduction anterogradly is blocked, meaning the wave of excitation can circle back round and re-excite the site of origin.
Can lead to palpatations.
Normally cells are refractory but in this case, reentry occur in a setting in which large differences of recovery from refractoriness exist between one site and another. The site with delayed recovery serves as a virtual electrode that excites its already recovered neighbor, resulting in a reentrant reexcitation.
What is heart block?
P-R interval shows a delay at AVN
1st degree: Means that the delay is slowed down, increasing the P-R interval (greater than 200ms). QS does still occur.
2nd degree: P-R interval becomes longer and longer, some impulses don’t get through (missed beats).
3rd degree: No association between P waves and QRS complexes. None of the signals reach either the upper or lower chambers causing a complete blockage of the ventricles. Escape rhythm in ventricles keeps you alive.
How can arrhythmias be classified?
According to their origin: sinus, atrial, nodal, ventricular
According to the heart rate change: bradycardia (slow) and tachycardia (fast)
What happens in sinus bradycardia and tachycardia?
In sinus bradycardia, there are fewer QRS complexes, gives beats per minute <60 (slowed down). Similar to what is seen in sleep or athletes.
In sinus tachycardia, there is an increase in the number of QRS complexes. BPM >100. Seen in exercise and stress.
What is atrial tachycardia?
Electrical impulse originates in atrial tissue different than the sinoatrial node. Rate faster than 100 bpm, although occasionally the rate may oscillate and be slower. Can be due to abnormal automaticity, triggered activity, or reentry in the atrial tissue. There are multiple p waves/atrial waves that are trying to hit AVN, but the ventricles can only respond to some of the hundreds fired from the atria. Gives a variable ventricular response.
What is ventricular tachycardia?
Classified by a rate of greater than 120 bpm and at least three wide QRS complexes in a row. The impulse is either being generated from increased automaticity of a single point in either the left or the right ventricle, or due to a reentry circuit within the ventricle. Most commonly caused by a scarring of the heart muscle by a previous myocardial infarction.
What is atrial fibrillation?
Rapid and irregular beating of the atria. Normal regular impulses generated by the SAN are overwhelmed by disorganised electrical impulses originating in the roots of the pulmonary veins. This leads to irregular conduction of ventricular impulses that generate the heartbeat. Atria show fibrillation rather than true P waves or atrial rhythm. Irregular ventricular response. Leads to the possibility of an atrial thrombus which can lead to a stroke. Treated with anti-coagulants.
What is ventricular fibrillation?
The heart quivers instead of pumping due to disorganised electrical activity in the ventricles that is so chaotic that the heart muscles can’t pump blood effectively. No defined rhythm or output. This type of heart condition is life-threatening, and must be treated immediately or the person will likely die. Treated with electrocardioversion to reset heart rhythm.
How is the heart control autonomically using sympathetic stimulation?
Sympathetic stimulation of the heart increases heart rate (positive chronotropy), inotropy and conduction velocity. Effects mediated by B1-adrenoreceptors that lead to cAMP activation which acts as an intracellular messenger. Increased slope of pacemaker potential so it is easier to reach the threshold potential. Increased automaticity (risk of arrhythmias).
How is the heart control autonomically using parasympathetic stimulation?
Parasympathetic stimulation of the heart reduces increases heart rate, inotropy and conduction velocity. Mediated by muscarinic (M2) acetylcholine receptors found in nodal and atrial tissue. Decreased slope of pacemaker potential, takes longer to reach the threshold level. Decreased automaticity. Inhibits atrioventricular conduction. Vagal tone (activity of vagal nerve) causes P-R interval increases because the vagal nerve slows the AVN, increasing the delay, slows firing of SAN too.
What is the Vaughan Williams classification of antiarrhythmic drugs?
- Class 1: Sodium channel blockers that preferentially affect channels that are in-use (wide open or refractory). Can be used to treat tachycardia. ‘Use-dependent’. These drugs can suppress heart function because electrical activation is intrinsically linked to contractility.
1a: disopyramide, quinidine, procainamide
1b: lidocaine, mexilitene
1c: flecainide, propafenone
-Class 2: B-adrenoreceptor antagonists (b-blockers)
Propanolol, nadolol, carvedilol: non-selective
Bisoprolol, metoprolol: B1-selective
- Class 3: Act to prolong the action potential (plateau phase) amiodarone and sotalol. Encourages refractory.
- Class 4: Calcium channel blockers: verapamil and diltiazem
What does digoxin do?
Digoxin is type of cardiac glycoside extracted from foxgloves. Acts to inhibit Na/K pump to slow heart.
Main effects:
-Bradycardia (increased vagal tone)
-Slowing of atrioventricular conduction (increased vagal tone)
-Increased ectopic activity, by blocking Na/K you end up with more Na inside the cell than normal, no Na gradient to activate Na-Ca pump, so more Ca stays within the cells.
-Increased force of contraction (caused by increased intracellular Ca)
Commonly used in atrial fibrillation to reduce venrticular rate response by blocking AVN. Used in severe heart failure as a positive inotropic.
What are the disadvantages of Digoxin?
Narrow therapeutic range (levels in blood must reach a certain point to be active).
Symptoms: Nausea, vomiting, diarrhoea, confusion.
What are the disadvantages of Class 3 anti-arrhythmia drugs?
Amiodarone and Sotalol (class 2 but has class 3 effects) can cause other cardiac arrhythmias.
- QT prolongation: longer time between Q and T. Can lead to a life threatening ventricular arrhythmia known as torsades de pointes which can result in sudden cardiac death.
- Polymorphic venrticular tachycardia: Form of ventricular tachycardia in which there are multiple ventricular foci with the resultant QRS complexes varying in amplitude, axis and duration.
What are the adverse effects of Amiodarone?
- Can cause QT prolongation and Polymorphic venrticular tachycardia
- Wide distribution in the body: can cause interstitial pneumonitis (large inflammation response in the lung)
- Abnormal liver function
- Hyperthyroidism/Hypothyroidism: iodine in drug interferes with thyroid metabolism
- Sun sensitivity: gives a high risk of burning
- Slate grey discolouration of skin (after 10/15/20 yrs)
- Corneal micro deposits: symptoms such as visual halos or blurred vision in as many as 10% of patients. Reversible.
- Optic neuropathy (damage to optic nerve): 2-fold increased risk. Characterised by an insidious onset, slow progression, bilateral simultaneous visual loss, and protracted disc swelling.
- Multiple drug interactions: protein bound in the bloodstream, can misplace other drugs
- Very large volume of distribution: take 3 months after terminating dosage before the drug leaves the body.
What is cardiac output and how does it change in exercise?
Cardiac output is the amount of blood pumped by the heart per minute. Can be increased by an increase in HR or volume per beat. Measured in litres/min.
Cardiac output = heart rate x stroke volume
Normally at rest it is 4.9 litres/min = 70 beats/min x 70mls. The total blood in the vasculature is 5 litres so the entire blood volume is pumped every minute.
BUT in exercise, ~35 litres/min so total blood pumps in less than 10 seconds.
What is ejection fraction?
Measured in %. Refers to the percentage volume of blood ejected with each cardiac contraction. Normally ~55-60% at rest, creating a reserve than remains in the heart.
In a heart failure patient, may only have an ejection fraction of 20/30%.
What are the key factors affecting heart rate?
- Sympathetic nervous system: when we start to exert ourselves, SNS instantaneously acts on SAN to increase HR and therefore CO.
- Parasympathic nervous system: decrease HR but doesn’t effect contractility.
- Circulating catecholamines (adrenaline & noradrenaline) slower than SNS because it takes time for adrenal gland to release and distribute catecholamines for effect on the heart.
- Drugs: for example salbutamol is a B-adrenoreceptor agonist which can act on the heart, as well as the lungs, to increase HR and CO.
What are the intrinsic factors affecting stroke volume?
Intrinsically the muscle has to be viable. In MI, this is not the case.
Intrinsic FACTORS
-Intracellular calcium: Acts to maintain plateau phase of AP but also initiates contraction through actin-mysoin action. Disturbing Ca, disturbs contractility.
-Oxygen, free fatty acids, ATP (nutrients): Must be available for the heart to function. In a failing heart, these things may be lacking.
What are the extrinsic factors affecting stroke volume?
Factors outside of the heart that affect its behaviour.
- Preload/filling pressure: Loading of the heart prior to contraction. Blood flow follows a continuous hydrolic system, pulsatile blood flow on arterial side which goes through the capillary bed and follows a continuous flow on the venal side. Blood filling is required for the heart to work. Measured by left ventricular end-diastolic pressure (LVEDP).
- Afterload: Resistance to ejection. Circulation has resistance due to the maintenance of BP by pre-capillary resistance vessels. Afterload determines how much blood the heart ejects according to that pressure.
- Sympathetic activity has a positive ionotrophic and chronotrophic effect. Independent of preload and afterload.
What is the role of calcium in the cardiac muscle?
L-type calcium channels are present in the cardiac muscle. Voltage-dependent (activated by AP) calcium channels are present on the PM of the cardiac cells. Calcium comes in but it is not enough, instead it acts as a trigger to cause the ryanodine receptors on the sarcoplasmic reticulum to release Ca from the store [chain reaction].
How does calcium cause cardiac muscle to contract?
Within the cardiac muscle, there are hundreds of actin filaments, covered with troponin and tropomyosin which block off its binding sites. When Ca is added, it binds to the troponin and the change in the configuration exposes the myosin binding sites. As myosin head binds to actin, release of Pi initiates ‘power-stroke’ whereby the myosin head changes conformation so that the filaments are forced to slide past one another. ADP is released and ATP binds, causing it to release actin.
Why are the actin-myosin crosslinkages important?
The actin-myosin crosslinkages are important because they
- Allow the AP to reach all of the muscle simultaneously
- Allow the whole muscle to contract simultaneously
What is the Frank-Starling mechanism?
Otto Frank and Ernest Starling
Frank performed work in frogs and found that if you stretch a cardiac cell before it is stimulated, it contracts more than if it was non-stretched. Starling found this to be the case in humans too.
The graph shows that increases in filling pressure/LVEDP/myocardial fibre stretching leads to an increase in the force of contraction which leads to an increase in stroke volume and cardiac output. (heart rate stays the same).
How do changes in preload affect the Frank-Starling mechanism?
Frank-Starling curve is relatively steep in a normal heart which means that if you have changes in venous return (preload) you simply move up (increase in VR) or down (decrease in VR), it doesn’t move the graph as a whole. Changes in VR don’t tend to have a major impact on CO because the SNS usually kicks in.
However in heart transplant patients, they don’t have SNS/PNS so CO is controlled by F-S mechanism or catecholamines.
How do changes in afterload and contractility (iontropy) affect the Frank-Starling mechanism?
The ventricle operates on a family of curves determined by afterload and contractility.
Curve moves down: If a patient suffers from a MI, they experience DECREASED CONTRACTILITY, reducing stroke vol. To rescue this, LVEDP increases to maintain CO. Same applies id you have an INCREASED AFTERLOAD. For example if you have an increased BP, there is an initial drop in SV causing LVEDP to increase.
Curve moves up: INCREASED CONTRACTILITY or DECREASED AFTERLOAD due to vasodilation causes the gradient of the curve to become steeper. Shows an increase in SV but decrease in LVEDP.
How do the effects of sympathetic stimulation affect the Frank-Starling mechanism?
Isoprenaline is a cardiac stimulant. if you give a cardiac muscle cell a stimulus, tension/contraction occurs due to increased Ca. However, if you have a background of a drug which is sympathomimetic the same stimulus gives an enhanced calcium influx and enhanced contraction. For any particular LVEDP there is a greater stroke volume under sympathetic stimulation.
No change in preload/afterload.
How do the effects of heart failure affect the Frank-Starling mechanism?
In heart failure, the curve is a lot flatter. In order to establish the F-S mechanism you have to increase the filling pressure with very little return in stroke volume. This increase in left ventricle pressure, eventually leads to increased pressure in pulmonary veins, leading to pulmonary oedema due to fluid escaping from the vasculature into the lungs.
Untreated heart failure may have both symptoms of pulmonary congestion and the fatigue due to a low cardiac output.
How do the effects of heart failure therapy affect the Frank-Starling mechanism?
Diuretics can bring the patient back down the curve to remove symptoms of pulmonary congestion, but have to be careful not to push them into low cardiac output symptoms.
ACE inhibitors can help by offloading the heart, causing vasodilation increasing the cardiac output.
Digoxin is a positive inotrope which acts to increase the contraction caused by the same stimulus. Puts the patient in a better CO state so you can use diuretics without pushing them into low CO.
What are the coronary arteries?
The arteries of the coronary circulation that transport blood into and out of the cardiac muscle. They are mainly composed of the left and right coronary arteries both of which give off branches and themselves branch from the aorta. On the surface of the heart within fatty layers (clinically easily accessible). Perfuse into the muscle.
How does pressure affect coronary blood flow?
Coronary blood flow = Perfusion pressure (difference between aortic diastolic pressure and LVEDP) / Resistance
Coronary flow only occurs in diastole because capillaries get squashed in systole.
How does cardiac oxygen consumption compare with other body tissues?
Arrested heart (alive, not contracting) = 2 Resting heart rate = 8 In heavy exercise = 70 Something has to change to allow for this mega change. Brain = 3 Contracting muscle = 50 Skin = 0.2 Heart is a really dynamic tissue, oxygen consumption changes a lot.
What contributes to cardiac oxygen delivery?
Oxygen delivery = Arterial oxygen concentration x Coronary blood flow
Very little oxygen dissolved in plasma.
Mainly determined by oxygen bound to haemoglobin
Anemia will cause reduced oxygen delivery.
Since breathing 20% O2 gives you a blood concentration of 98% O2, can’t increase that much more so coronary blood flow is the primary determinant of O2 delivery.
What does an aortic pressure trace show?
You can get a direct trace of arterial BP using an arm catheter. Every time the heart beats there is a change in pressure. Peak in pressure is systolic BP.
When it relaxes, pressure doesn’t drop to 0 because the aortic valve closes, maintaining a certain level of pressure (diastolic BP kept at about 80). Important that this is maintained (in aorta and hence all branches) so that you can get perfusion to the cardiac muscle.
What does a left ventricular pressure trace show?
As the left ventricule contracts, pressure wave reaches about 120. As it relaxes there is nothing to support diastolic pressure so pressure drops to almost zero, but as diastole is occuring ventricle is filling from the atria so it never truly reaches zero.
What does a Left ventricle to aorta pressure trace show?
There is the same systolic blood pressure between the two. However, the diastolic pressures are very different.
Arterial diastolic BP = 70 LVEDP = 10 This pressure difference causes perfusion.
The window for coronary flow is between the two systoles. There are physical, local, nervous, humoral factors that can affect the size of the window.
It can become bigger in either direction (if time is longer (HR) or if the gradient is bigger), this leads to more perfusion.
What are the physical factors influencing diastolic coronary flow?
Time of systole doesn’t tend to change majorly but diastole does.
-Tachycardia: disproportionately reduces diastole by reducing time
-Raised LVEDP: Due to high BP. Decreases perfusion pressure by moving bottom ventricle line upwards
-Reduced diastolic pressure: Decreases perfusion pressure by moving arterial top line downwards
ALL narrow the window for coronary flow. Patients with coronary artery disease can be fine at normal rest but will be symptomatic when exercising.
What is autoregulation of coronary blood flow?
Ability of an organ to maintain a constant blood flow despite changes in perfusion pressure.
Coronary blood flow = Perfusion pressure / Resistance
If perfusion pressure begins at 100mmHg but drops suddenly due to septic shock, blood loss etc, there is a reduction in flow. You would think that this causes an increase in resistance but this is not the case because of autoregulation. Autoregulation means that the heart dilates the resistance circulation. This causes the flow to increase to an almost recovered level. This is maintained despite the reduced pressure.
Autoregulation cannot occur if perfusion pressure is too high or too low. But there is a good sized window where it can recognise a drop in partial pressure of O2 reaching the heart.
How does local metabolites and mediators control the vasculature?
Local control by metabolites are most important. Hypoxia (low pO2) causes a marked increase in coronary vasodilation in situ but not in an isolated coronary artery in vitro. This suggests that its not a property of the arteries themselves but of the local metabolites, namely adenosine.
There are others which will build up when metabolism isn’t fully aerobic: potassium ions, carbon dioxide, hydrogen ions, lactic acids.
What is the neural and humoral control of the vasculature?
Less important.
In larger vessels, this is mediated by a-adrenoreceptor which causes vasocontriction.
In smaller vessels, this is mediated by B2-adrenoreceptors which causes vasodilation.
How does coronary artery disease affect the perfusion pressure?
This can be caused by one major stenosis of a coronary artery or in a more diffused fashion, multiple stenosis cause a ‘string of sausages’ look.
If you have the correct perfusion pressure but have stenosis you won’t have the reserve to supply the heart in activity.
Why is the heart an endocrine organ?
The heart produces cardiac natriuretic peptides in response to stretch, increased pressure or volume overload.
- Atrial natriuretic peptide (ANP) is produced in granules in atria that respond to stretch.
- Brain natriuretic peptide (BNP) is produced by the ventricles in response to stretch.
- C natriuretic peptide is produced by the endothelia
What are the main effects of the cardiac natriuretic peptides?
- Increase the renal excretion of sodium (natriuresis) and sodium (diuresis)
- Relax vascular smooth muscle: dilates afferent, constricts efferent which increases perfusion pressure
- Increased vascular permeability
- Inhibit the release and actions of Aldosterone, Angiotensin II, Anti-diuretic hormone
- Acts as a counter-regulatory system to the renin-angiotensin system
How are cardiac natriuretic peptides manipulated in heart failure treatment?
Cardiac natriuretic peptides are metabolised by neural endopeptisade (NEP, neprilysin). NEP inhibition increases levels of natriuretic peptides.
Entresto is a heart failure drug that combines the action of Sacubitril (neprilysin inhibitor) and Valsartan (Angiotensin II blocker). Allows for vasodilation and increase in cardiac natriuretic peptides.
What is the definition of heart failure?
NICE: Complex clinical syndrome of symptoms and signs that suggest that the efficiency of the heart as a pump is impaired.
ESC guidelines: Abnormality of cardiac structure or function leading to failure of heart to deliver oxygen at a rate commensurate with requirements of metabolising tissues despite normal filling pressures/at the expense of increased filling pressures.
Secondary to coronary artery disease and/or MI, kidney failure, sleep apnea, viral infections which may cause loss of muscle activity,
What is the epidemiology of heart failure?
1 million cases in the UK
50% increase predicted in the next 25 years due to the aging population (by 2032 16m will be over 65 - 23%). It is a disease of the elderly, rarely seen below 65 years, very common over 80.
More common in men, MI more common in men, MI may lead to HF.
70% of HF budget towards hospitalisation which may require 2/3/4 weeks.
What is the prognosis for HF and what are the aims seeking to tackle it?
Poor prognosis >30% mortality within 1 year, then 10% per year. From 1988 to 1999, prognosis did improve for HF, but it still carries a similar prognosis to colorectal and breast cancer.
Key aims include: Keep people out of hospital, keep people from dying, keep people free from symptoms. It is more cost-effective to develop drugs to keep people out of hospital.
What are the different types of heart failure?
Majority of HF patients have LVSD (left ventricular systolic dysfunction) meaning the ventricle doesn’t contract properly usually due to a heart attack.
Others have HFPEF (HF with preserved ejection fraction) whereby there is an abnormal diastolic function, which manifests as an increase in the stiffness of the heart’s left ventricle and a decrease in left ventricular relaxation when filling with blood before the next beat.
Most evidence for pharmacology is in chronic HF due to LVSD.
What is acute and chronic heart failure?
Acute HF: something has suddenly happened to cause the HF
Chronic HF: long-term problem over weeks and months, alternate between well, unwell, well etc
What does HF treatment target?
Main benefit is with vasodilator therapy via neurohumoral blockade (RAAS-SNS) and not from direct left ventricular stimulants. Following an insult to the heart (e.g. MI) you get a RAAS-SNS response. So best treatment is to target this response.
What is the difference between heart failure and LV dysfunction?
They are related but separate entities, you can have one without the other.
You can see and measure LV dysfunction using an echocardiogram but HF is seen in the signs and the symptoms in the patient.
What are the signs and symptoms of heart failure?
-Reduced cardiac output (forward flow) means patients experience fatigue and exercise intolerance.
-Increased filling pressure (backward pressure). If output is impaired, filling pressure increases, heart dilates, increased pressure in pulmonary vein upstream of ventricles leading to pulmonary oedema. Patients want to be sat up to use all respiratory muscles.
More commonly have chronically raised left atrial pressure (chronically congested).
Breathless on exertion.
If the right ventricular end diastolic pressure is raised you can see a raised jugular vein (pressure is reflected because there are no valves).
When the pressure on the right side goes up, all venous pressure increases, congesting the liver, peripherally at the ankles. Also causes anasarca and ascites.
How does heart failure affect the Frank-Starling curve?
The curve is depressed for HF patients. Have the risk of experiencing pulmonary congestion and hypotension caused by low cardiac output. Diuretics and vasodilators can work to reduce preload without leading to abnormally low CO.
What are the different types of diurectics?
Help you lose Na and water to tackle oedema. Can be used in HF and Hypertension.
CLASSES:
-Thiazides and related drugs (act on distal tubule): weak diuretics, used more in hypertension
-Loop diuretics (act on loop of Henle): very powerful, used for HF
-Potassium-sparing diuretics: diuretics usually end up depleting K so these were developed to relieve loss of K
-Aldosterone antagonists: weak diuretics, antognises Aldosterone which is part of RAAS
What are the main Thiazide, Loop and potassium-sparing diuretics?
Thiazide and related diuretics: Bendroflumethiazide, Hydrochlorothiazide, Chlorthiazide
Loop diuretics: Furosemide and Bumetanide (better absorbed)
Potassium-sparing diuretics: Spironolactone, Eplerenone (aldosterone antagonists which also spare K). Amiloride and Triamterine (older tend not to be used).
Why is Eplerenone often used instead of Spironolactone?
Due to the chemical structure of Spironolactone, it has an eostrogen-like effect. Small percentage of men can get enlarged and painful breast tissue (gynecomastia). Eplerenone is more expensive but doesn’t give these effects.
What are the main adverse effects of diuretics?
- Hypovolaemia and Hypotension (mainly loop diuretics)
- Hypokalaemia
- Hyponatraemia
- Hypomagnesaemia
- Hypocalcaemia
- Erectile dysfunction (mainly thiazides)
- Raised uric acid (hyperuricaemia - gout crysts in joints)
- Impaired glucose tolerance, increase instance of diabetes
What do vasodilators do for HF patients?
Vasodilators act to reduce the resistance (afterload) to increase cardiac output. Hydralazine (decreases blood pressure) combined with Isosorbide dinitrate (nitrates dilate veins and arteries). Dinitrate is metabolised to mononitrate so now we just used isosorbide mononitrate.
Give an example of a study that proved the effectiveness of vasodilators for HF patients?
Trial in 1986: Effect of vasodilator therapy oon mortality in chronic congestive heart failure
Used 642 men with HF symptoms.
Given either placebo, prazosin (a-blocker) or combination of hydralazine and isosorbide dinitrate. Placebo and prazin group were almost identical but the combination did significantly reduce mortality (36% 3 year reduction) and improved ejection fraction.
What are the compensatory mechanisms to heart failure?
In response to heart failure…
- Cardiac: loss of arterial pressure, cardiac output, loss of perfusion to the kidneys
- Systemic: this activates the baroreceptors which activate the sympathetic nervous system and the Renin-angiotensin-aldosterone system
How does blood loss activate the SNS and RAAS?
Compensatory mechanism is thought to be targeted to blood loss rather than heart failure as it is a relatively new phenomenon. In blood loss, you lose volume, venous return to the heart decreases, preload decreases, BP decreases and there is decreased perfusion to the kidneys, this activates the baroreceptors and leads to SNS (fast) and RAAS (slow).
What is the SNS response and RAAS response to blood loss and how do they interact?
In RAAS, Angiotensinogen is converted to Angiotensin I using Renin, then Angiotensin I is converted to Angiotensin II using ACE. Angiotensin II is a powerful vascontrictor which also leads to salt retention, aldosterone release and tubular sodium reabsorption leading to sodium and water retension.
SNS releases noradrenaline which acts to increase cardiac output and peripheral resistance, acting to control blood pressure.
SNS (noradrenaline) also positively encourages the action of Renin, increasing the levels of Angiotensin I. Angiotensin II also increases peripheral resistance and cardiac output reinforcing SNS action.
What effects do the SNS and RAAS provide in acute blood loss?
- Tachycardia: increased cardiac output
- Positive inotropic effect: increased cardiac output
- Vasoconstriction: increased blood pressure
- Sodium and water retension: increased circulatory volume
Which is ALL GOOD!
What effects do the SNS and RAAS provide in LV systolic dysfunction?
Initiates same response to acute blood loss.
- Tachycardia: increased workload and O2 demand
- Positive inotropic effect: increased workload and O2 demand
- Vasocontriction: increased afterload
- Sodium and water retention: increased preload and oedema
- Chronic adrenergic stimulation (bathed in noradrenaline): myocyte toxicity and arrhythmia
Which is ALL BAD!
What are the different drugs that can interfere with the RAAS?
- Aldosterone antagonists prevent aldosterone and angiotensin II from being produced in the first place or block them.
- ACE inhibitors block serum ACE in order to block the RAAS pathway to a certain extent
- AR blockers can block angiotensin II that has got through
- B-adrenergic antagonists can be used to block the sympathetic neurous system (noradrenaline action)
- Renin inhibitors are used for hypertension
Give an example of a study that proved the effectiveness of aldosterone antagonists for HF patients?
Spironolactone in Heart failure. Rales study in 1999
Drug vs. Placebo in blind trial
Count the number of death over 36 months
HF have a natural history of 75% survival after 1 year.
Curves diverge early (within 2-3 months) and continue to diverge showing a significant increase in survival probability of the patients.
Give some examples of studies showing the effectiveness of ACE-inhibitors in heart failure?
- 253 patients with severe heart failure. Enalapril vs. placebo. At 12 months, patients normally have 60% mortality, treatment reduces mortality to 40%.
- 2006 patients with heart failure following a MI. Ramipril vs. placebo. At 12 months, patients normally have 30% mortality, treatment reduces mortality to 20%.
- Mild-moderate heart failure group. Enalapril vs. placebo. At 12 months, patients normally have 10% mortality or hospitalisation, treatment imprpoves both.
Therefore, irrespective of the the level of heart failure, there is a benefit from ACE inhibitors.
What are ACE inhibitors?
Used for hypertension, heart failure and diabetic neuropathy.
Key ACE inhibitors: Ramipril, Perindopril, Enalapril and Trrandolapril.
Usually 1 a day but in HF it is good to split the dose because you need the function 24/7 unlike in hypertension where it isn’t really a problem at night,
What are the main adverse adverse effects of ACE inhibitors?
- Related to reduced angiotensin II formation: Hypotension (AGII usually supports circulation), Acute renal failure (AGII usually supports glomerular filtration pressure), Hyperkalamia (Aldosterone usually causes K loss), teratogenic effects in pregnancy.
- Related to increased Kinins: cough (10% of people have dry cough that last for duration of dose), Rash, Anaphylactoid reactions - angioedema/other allergic response.
This is because ACE is a very non-specific enzyme so as well as converting AGI to AGII it also breaks down bradykinin into inactive peptides.
What are ARBs?
Angiotensin II Receptor Blockers (ARB)
Hypertension (mainly) and Heart failure (used when ACE-I contraindicated or gives side effects). Candesartan, Valsartan, Losartan, Irbesartan, Telmisartan.
Main adverse effects: Symptomatic hypotension (especially in vol depleted patients), Hyperkalaemia, Potential for renal dysfunction, Rash, Angio-oedema.
Generally well tolerated.
Contraindicated in pregnancy.
Angiotensin II acts on the AT-1 receptor, ARB blocks it at the receptor level.
How have B-blockers been trialed in heart failure?
US Carvedilol HF study 1996. Tested in a milder heart failure group, showed that you have increased probability of survival with Carvedilol. Mortality benefits have been shown for Carvedilol, Bisoprolol and Metoprolol.
Probablity of event-free survival is important to consider. Other B-blockers haven’t been trialled in such a rigorous way, hence they are not licenced in the same way.
Use very low doses of B-blockers to prevent collapsing of stimulation.
Give an example of a study that shows the effectiveness of Digoxin in heart failure?
Digitalis Investigation Group in 1997. Placebo vs. Digoxin. In terms of 12 month mortality there is very little change. But looking at death or hospitalisation due to worsening heart failure shows that Digoxin is beneficial. Can be used as an add-on when other drugs are just not working.
How is Ivabradine used in heart failure?
Lancet study (2006). If is the funny current. It behaves differently to other channels and controls intrinsic sinus node pacemaker. Ivabradine can block If current, slowing sinus node rate. Used in angina and heart failure (HR>70).
How can Sacubitril/Valsartan (Entresto) be used in Heart Failure?
Sacubitril = neprilysin inhbitor
Valsartan = angotensin II blocker
Neprilysin inhibition increases levels of natriuretic peptides. When it is trialled it is tested against Enalapril (no longer ethical to used a placebo). Benefit for heart failure patients is small but is there!
How do you treat acute heart failure?
Following a MI, heart failure can lead to serious pulmonary oedema and breathlessness.
-Oxygen
-Diamorphine for pain
-Nitrates to reduce preload/afterload, vasodilator
-Loop diuretics
You CANNOT give them ACE inhibitors or B-blockers because they are dependent on the sympathetic drive to keep them alive.
-Inotropes (for a very short period) - adrenergic agonists and PDE III inhibitors.
What are the inotropes that may be used for a short while in acute heart failure?
Inotropes:
- Adrenergic agonists including Inoconstrictors (Noradrenaline, adrenaline, dopamine) and Inodilators (Dobutamine, Dopexamine, Isoproternol)
- PDE III inhibitors which will stimulate cAMP
What is the outcome of the study testing the effect of a PDE III inhibitor?
Promise study in 1991, treated HF patients with Milrinone vs. Placebo. At the 12 month mark, placebo survival probablity is 60%, but Milrinone survival probablity is 45%. People do worse on this drug so patients are highly monitored. An ethical group will remove patient from treatment if it is worse than the disease. Stimulation of a failing heart is usually a no-go but can be used for very short time in acute heart failure.
Why is the vasculature important?
The vasculature organises the delivery of oxygen/nutrients and removal of excretory products.
- Arterial contraction/relaxation regulates blood pressure
- Understanding mechanisms to identify drug targets
- Artery wall dysfunction underlies pathophysiology particularly in artherosclerosis and hypertension
What is the structure of the artery?
Large arteries - arterioles - capillaries - venules - large veins
Artery structure has a lumen in the middle. The wall is composed of many layers. Thinnest layer is endothelium, the tunica intima, tunica media and tunica externa. There is elasticity present between layers allowing for movement for pulsatile pressure. Outer layer has fibrous collagen giving a more rigid structure for the artery.
Vascular smooth muscle allows for contraction. There is important communication between the smooth muscle cells and endothelium.
What is the endothelium?
Cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. It is a thin layer of simple squamous cells called endothelial cells. Largest organ - covering football pitch in an adult human.
Mediates BP. Dysfunctional/activated endothelium can lead to early stages of disease.
What is the glycocalyx?
Lubricant layer on the endothelia of the blood vessels.
Intact in a non-activated endothelium
Anti-coagulant
Prevents circulating cells from binding to adhesion molecules on the endothelial surface.
When is the glycocalyx shed?
The glycocalyx is shed when the endothelia is activated/dysfunctional. This occurs in response to inflammation, injury, healing, MMPs. This allows for the binding of adhesion molecules as the adhesion receptors are exposed without the glycocalyx. Monocytes can enter the artery wall. This initiates/progresses atherosclerosis in the presence of oxLDL.
Also occurs when there is disturbed blood flow. When vasculature is straight, blood flow has the same pressure exerted on the artery wall. But when there are bends or ‘shoulder regions’ there is disturbed blood flow. Loss of glycocalyx and prone to plaque development.
What happens in healthy endothelial cell signalling?
ACh, Histamine, 5-HT, Bradykinin can bind to various receptors to cause an increase in Ca in the cell. This activates endothelial NO synthase to convert argenine to NO. NO leaves the cell and acts on other cells in the surrounding environment. High shear (blood flow) also activates NO production by increasing Ca.
What happens in activated endothelial cell signalling?
IL-1, Thrombin, Endotoxin can activate various receptors to cause the production of endothelin 1 which can be released from the cell. There is also the upregulation of various transcription factors causing an increase in ROS, ICAM-1, VCAM-1, IL-8 and COX2. The increase in these molecules is also caused by disturbed blood flow. These molecules cause an increase in adhesion molecules causing an increase in monocytes.
How does vascular smooth muscle contract?
Ca is REALLY important! Ca ATPase present in the PM and acts to pump Ca out, there are also calcium channels in the PM that allow Ca entry. Sarcoplasmic reticulum stores calcium and contains Ca-ATPase on its membrane to pump Ca in. Activation of Ca channel on PM causes an influx of Ca down concentration gradient. It interacts with calmodulin and activates myosin light kinase. MLCK phosphorylates inactive myosin which activates myosin. Actin crossbridge cycle starts leading to contraction.
What are the contractile stimuli that lead to vascular smooth muscle contraction?
There are other ways which can cause a release of calcium such as receptors that activate second messengers like IP3 which acts on the Ca channel on the sarcoplasmic reticulum. These include GPCRs for endothelin A/B, TP (prostanoid), AT1 (angiotensin), histamine and noradrenaline (a-AR) which all cause production of IP3.
Calcium channels on the PM include voltage-selective (L-type), receptor generated (e.g. P2X), TRP channels and store-operated channels (Ora1).
What mediates vascular smooth muscle relaxation?
3 important mediators: cyclic GMP (produced by guanylyl cyclase), cyclic AMP (produced by adenylyl cyclase) both of which cause a decrease in Ca. Thirdly K channels produce a K efflux that causes hyperpolarisation which also causes a decrease in Ca.
How does cGMP lead to vasculature smooth muscle relaxation?
Guanylyl cyclase is activated by nitric oxide from endothelium and synthises cGMP. Increased cGMP can act in two ways to lead to relaxation. cGMP leads to activation of Protein Kinase G which increases the activity of myosin phosphatase. This means that active myosin is converted back to inactive myosin leading to muscle relaxation. Also cGMP decreases Ca which means no association with MLCK, meaning that active myosin is not produced - no contraction.
How does cAMP lead to vasculature smooth muscle relaxation?
G-coupled receptors for B-agonists, Adenosine, prostaglandins activate adenylyl cyclase which synthesises cAMP. cAMP decreases Ca which means no association with MLCK, meaning that active myosin is not produced - no contraction.
How does K efflux lead to vasculature smooth muscle relaxation?
In smooth muscle cells there are different K channels that you can having, including BK channels (large conduction), SK (small conductance) or B-agonists (via BY of G protein). The K efflux leads to hyperpolarisation which decreases intracellular Ca which means no association with MLCK, meaning that active myosin is not produced - no contraction.
Why are phosphodiesterase enzymes important in vascular smooth muscle contraction/relaxation?
Phosphodiesterase enzymes hydrolyse cAMP and cGMP so are important in regulating these pathways.
What are the endothelial mediators that regulate smooth muscle cell contractility?
These mediators are often released by the endothelium which will cause contraction or relaxation of the artery via smooth muscle cells. They include nitric oxide, prostanoids, endothelin, angiotensin II.
How does nitric oxide regulate smooth muscle cell contractility?
NO regulates blood pressure and regional blood flow. eNOS is found in carveola of endothelium activated by blood-bourne mediators. eNOS is impaired by:
-Smoking
-High glucose and insulin
-oxLDL depletes cholesterol from carveola leading to a loss of eNOS and a raised blood pressure.
These are therefore all risk factors for cardiovascular disease.
How do prostanoids regulate smooth muscle cell contractility?
Prostanoids are produced from the precursor arachidonic acid by COX1/2 to Prostaglandin H2. COx activity is activated by influx of Ca or increased ROS. PGH2 can produce Thromboxane A2 which is released from the endothelial cells and acts on the TP receptor on the membrane of the VSM cell. TP receptor activates PLC producing IP3 which activates Ca release from sarcoplasmic reticulum. Leading to MLCK conversion to active myosin and contraction!
PGH2 can also produce PGE2 which acts on EP-R (the type 1-4 depends on the vasculature bed). Different types can either activate or inhibit adenylyl cyclase so may or may not increase cAMP. PGI2 is also produced which can act on IP-R which activates Gs proteins activating adenylyl cyclase and increasing cAMP leading to relaxation!
So, prostaglandins can either lead to contraction or relaxation depending on which enzymes are expressed and which prostanoids are produced from PGH2.
How does Endothelin-1 regulate smooth muscle cell contractility?
Precursor is ‘big endothelin’ in endothelial cells which is transcriptionally upregulated by many different stimuli. These include IL-1, Thrombin, Glucose, OxLDL, Insulin, Angiotensin II, Cortisol, Adrenaline and Hypoxia.
Endothelin converting enzyme cleaves big endothelin to make endothelin 1. ET-1 is the active mediator that acts on smooth muscle. Can act on ETa or ETb receptors (both expressed on VSM). Both lead to production of PLC and therefore IP3. Increased Ca leads to contraction.
What is the negative feedback mechanism for Endothelin-1 production?
Endothelial cells themselves also have ETb receptors so when Endothelin1 is produced it can act back on the endothelial cells. This causes an increase in Ca in endothelial cellsand the activation of eNOS. NO inhibits the ECE (neg feedback) but also freely diffuses to VSM cells to cause relaxation, opposing usual effect.
Since ETb can lead to contraction and relaxation if you want to therapeutically target contraction should ETa.
How does Angiotensin-II regulate smooth muscle cell contractility?
Angiotensin II is produced by certain types of endothelial cells specifically in pulmonary and renal vasculature. ACE is expressed on the surface of the endothelial cells and converts circulating angiotensin I into angiotensin II by cleavage. Angiotensin II then acts on AT1 receptors on VSM cells. AT1 receptors couple to PLC and produce increased IP3 and therefore increased Ca and contraction! Activation of AT-1 receptors also activates MAPK pathways which give a more persistant long-term change in the vasculature (contractile response).
What changes in the vasculature in ageing and disease?
-Atherosclerosis: endothelial cells become further away from the VSM cells that they regulate, so atery wall is less able to respond to normal vasculature mediators for contraction/relaxation.
Increased immune cells in artery walls release factors which cause VSM cells to proliferate in a disordered manner.
-Loss of glycocalyx due to increased LDL or areas prone to atherosclerosis
-Calcification: Ca deposits build up with age which stiffens the artery preventing it from being able to contract/relax in a coordinated manner.
-Loss of elastin with age
-Decrease in NO due to age, smoking, hypoxia
ALL of the above lead to increase blood pressure.
