RBF Flashcards
What is respiratory failure?
When the lung fails to oxygenate the arterial blood adequately and/or fails to prevent undue CO2 retention
What are the causes of hypoxaemia?
Reduced PiO2 Hypoventilation VQ mismatch RL shunt Diffusion problem
What can cause hypoventilation?
Decreased respiratory drive
Neuromuscular incompetence- due to issues with nerves themselves, NMJs or the muscles (electrolytes, malnutrition, length tension abnormalities)
Or abnormal load- do due increased resistance, elastence, chest wall elastic load, or minute ventilation load
What is the alveolar gas equation?
PAO2 = (Pb - PH2O) x FIO2 - PACO2/R + k
At sea level on air this equates to
20 - PaCO2/0.8 - PaO2
What is alveolar capillary block and how does it cause SOB exacerbated by exercise?
It is due to buildup of scar tissue etc in the interstitial space between the alveolar wall and the capillaries, making it more difficult to diffuse O2 from the air into the blood
Normally, it takes a small amount of time for the saturation of blood to near the PAO2 as it travels through the pulmonary capillaries
In cases like these, it takes longer to reach equilibrium. When the patient exercises, it results in even less transit time, meaning the blood often leaves less saturated than normal
How can diffusion issues cause hypoventilation?
Alveolar capillary block- diffuse interstitial lung disease
Capillary volume/Hb issues- pulmonary hypertension and anaemia
Loss of diffusing surface- emphysema
What are the equations related to diffusion in the lungs?
Vgas = A/T x D x (P1-P2)
D =Sol sqMW
1/DLCO = 1/DM + 1/O x VCapillary
What are the different stages of Oxygen consumption affected by?
PiO2 is affected by altitude and fraction of O2 in the air
PAO2 depends on alveolar ventilation and PACO2- it’s a pump, so can show a normal A-a gradient even with respiratory failure
PaO2 is affected by gas exchange, in the A-a gradient. This is impacted by VQ mismatch, RL shunt and diffusion factors
Tissue PO2 is affected by extraction, perfusion, and Hb or saturation
What is homeostasis and how is it managed?
The capacity to regulate the internal environment to maintain stable, constant conditions
It is actively controlled, with feedback mechanisms regulating the output of a process, and sensors detecting this to feed back to modulate the actions of an effector
What is equilibrium and how does this relate to the cardiovascular system?
Closed systems containing two or more processes whose outputs are determined by a common parameter can operate at a stable equilibrium
Eg. MRAP affects the extent of right heart filling (and CO) as well as amount of venous return
As MRAP increases, VR falls and CO increases to a max.
As MRAP falls, CO falls and VR rises until the pressure inside the veins is equal to outside- this is when they begin to close off and a plateau is formed
They must operate at an equilibrium where VR is the same as CO
How does cardiovascular equilibrium change?
During exercise, there is a degrease in PVR and an increase in venous muscular activity, helping to drive blood back to the heart. This causes an increase in MRAP, so increased cardiac filling and an increase in equilibrium point
More vigorous cardiac function causes a reduction in MRAP, allowing an increased venous return until the point of plateau
How does circulatory distribution change during exercise?
Resistance to blood flow changes, preferentially diverting blood to the muscles and heart at the expense of the GI tract, kidneys and liver.
Blood to the brain remains the same
How does the ANS affect cardiovascular homeostasis?
The CNS has receptors around the body that receive information and feed it back to the brain.
It can then activate sympathetic or parasympathetic nerves to modulate the function of specific organs
Describe the RAAS system and what activates it
Renin is released from the JGA due to sympathetic stimulation, decreased arteriolar pressure, or decreased sodium at the macula densa
This converts angiotensinogen to angiotensin I, which is then converted by ACE in the lungs to angiotensin II
What are the actions of angiotensin II?
Activates sympathetic pathways in the brain as it crosses the BBB
Facilitates neurotransmission at paravertebral ganlia
Increases synthesis and release of NA
Acts to cause constriction of vascular smooth muscle
Increases formation and release of aldosterone to increase absorption of sodium in the renal tubules- increases fluid retention and blood volume
Facilitates ADH secretion and stimulates thirst
What are the actions of ADH?
Regulates renal water handling
Can act as a vasoconstrictor
Where are ANP and BNP synthesised and in response to what?
ANP= Atrial myocytes
BNP- ventricles
Stimulated in response to cardiac distension, sympathetic stimulation, angiotensin II or endothelin
What are the actions of the natriuretic peptides?
Natriuresis and diuresis increased GFR and filtration fraction Inhibition of renin Vasodilation Results in reduced blood volume, arterial pressure, central venous pressure, pulmonary capillary wedge pressure and cardiac output
What does NEP do?
A circulating enzyme that degrades natriuretic peptides. Inhibiting it increases and potentiates natriuretic peptids
What is the use of anticoagulant drugs?
Used for arterial disease such as CAD, cerebrovascuular disease, and peripheral vascular disease
Used in thrombo-embolic disease, for atrial fibrillation, DVT/PE, and for prosthetic cardiac valves (metal only)
Describe unfractionated heparin and what it can be used for
It is a large molecule with variable weights (as it is produced in different animals’ tissues)
It is an ionic compound so it should always be given IV
Used for acute coronary syndromes, in thromboembolism and as a temporary warfarin replacement during pregnancy
How does unfractionated heparin work?
It binds to and increases the activity of anti-thrombin III, which inactivates thrombin, Xa, IXa, XIa and XIIa
This requires its dosing to be monitored with APTT
It has a rapid onset and offset with a short half life but variable bioavailability- it may bind unpredictably to cells and plasma proteins
Must be maintained within a therapeutic range of 50-80s APTT
What are some adverse effects of unfractionated Heparin and how does it get reversed?
It can cause bruising or bleeding
Heparin induced thrombocytopenia- and autoimmune phenomenon as heparin epitopes are similar to platelets, resulting in bleeding or serious thromboses.
Requires checking of platelets every 2 days
Heparin is reversed by giving protamine (dissociates heparin by irreversibly binding) if actively bleeding, otherwise simply stopping heparin will be enough after 30 mins.
Describe low molecular weight heparins and its advantages
Generated by depolymerisation of unfractionated. They bind to antithrombin III but do not inactivate thrombin, specifically acting on Xa.
It has a reliable dose-effect relationship and does not require monitoring.
It has a higher bioavailability and doesn’t bind to other blood proteins etc
Longer biological half life, given subcutaneously so can be done at hospital and home, and has lower risk of thrombocytopenia and bleeding
Dosing is also only based on weight rather than APTT
What are the pros and cons and uses of LMWH compared to UF heparin
Pros are improved pharmacokinetics, less monitoring requirement, as well as less risk of thrombocytopenia and osteoporosis
Cons are that APTT cannot be used to monitor it, it cannot be reversed by protamine, and it is harder in renal failure as LMWH are cleared by kidneys while UF heparin is cleared by reticuloendothelial system
Both are used in stemi, initial DVT/PE, and as a warfarin alternative. LMWH is also used for catheterisation and nstemis.
What is warfarin and how does it act?
It is a vitamin K antagonist, with S isoforms more active than R
It inhibits synthesis of coagulation factors VII, IX, X and II, but has a slow onset- so while it is waiting to kick in, heparin is used
It is metabolised by CYP450 and crosses the placenta
What is warfarin used for and for how long?
It is used for thrombses, and for preventing these in cases of mechanical heart valves and atrial fibrillation (lifelong)
In terms of warfarin duration of treatment in DVT, it used for months for risk factors or first DVT. It is used lifelong in thrombophilia and potentially cancer cases
What are the side effects of warfarin?
Intracrainal or GI haemorrhage (more likely in oder age groups, those with cerebrovascular disease, previous GI ulcer/bleed, liver/renal damage, and high target INR
Contraindicated by pregnancy, high risk of haemorrhage (uncontrolled alcohol, dementia, high falls)
How is warfarin monitored?
By INR: Ratio of patient’s PT to mean normal PT.
Those with prosthetics and recurrent thromboses have a higher target INR than those with a single venous thrombosis episode
What are some interactions with warfarin?
Most increase effect of warfarin’s effect by inhibiting CYP450
Eg. intermittent alcohol, analgesics, amiodarone
Some inhibit warfarin by increasing P450- eg. prolonged alcohol, barbituates
How can warfarin (High INR) be reversed?
Giving vitamin K if bleeding is not severe Giving prothrombinex (concentrate containing vitamin K dependent factors) if lifethreatening
What are some of the downsides of warfarin?
Narrow therapeutic window
Lifetime risk of haemorrhage increases
Drug interactions
Needs regular INR
Describe dabigatran and its usage
It’s a prodrug that is converted to an inhibitor of coagulation by gut, plasma and liver esterases
It isn’t P450 dependent, but is excreted renally
It is used to treat and prevent VTE, for atrial fibrillation, but NOT for mechanical valves
Bleeding can be managed by monoclonal IV antibody idarucizumab
Describe VQ mismatch and what it means for CO2 and CCO2
VQ mismatch is a ratio of the perfusion of alveoli to their ventilation
An alveolus that is ventilated but not perfused has a ratio of infinity, and can be considered dead space as it does not affect gas exchange at all
An alveolus that is perfused and ventilated has a ratio of 1, and gives a normal CO2 and CCO2.
An alveolus that is perfused but not ventilated has a ratio of 0, and is called venous admixture, as the blood being combined in later circulation is technically venous. It has a low CO2 and high CCO2.
Overall, this has the effect of slightly lowering CO2 and keeping CCO2 normal (due to the shape of its dissociation curve). However, this regulation is decreased in a loss of competence or introduction of an abnormal load.
Describe COPD and its effects
It is characterised by airflow obstruction that is not fully reversible
It is progressive, related to an abnormal inflammatory response
Symptoms include chronic mucus hypersecretion, emphysema and small airway inflammation, with increased and hypertrophied goblet cells and destruction of lung parenchyma
What happens of a poorly ventilated alveolar system becomes worse or abnormal load is introduced?
PaCO2 will increase, causing a loss of CO2 drive and respiration to depend on hypoxic drive
If O2 is administered due to SOB, it will cause loss of drive, causing reduced ventilation, hypercapia, and potentially respiratory and metabolic acidosis.
CO2 increases can show intracellular acidosis, hypoxia, and sleep depravation.
What are the consequences of a respiratory acidosis?
Reduced cardiac and respiratory muscle contractility, reduced endurance time, arterial vasodilation, increased cerebral blood flow, arrhythmias etc.
What is the difference in oxygen and co2 dissociation curves and what does this mean?
Oxygen’s dissociation is sigmoidal, but normally CO2 is on the high side, so when hyperventilating, the Co2 only moves along the flat part of the curve
CCO2 is diagonal, so when PCO2 decreases during hyperventilation, CCO2 also decreases
Describe RL shints
It is an anatomical abnormality shnting blood from the RHS to LHS of the heart
Distinguished from VQ mismatch b administering 100% O2- VQ mismatch will always increase with 100% O2, while a shunt increases much less as it worsens
This is because the shunted blood does not see the added O2, and so depresses the arterial PO2- however, it can still help by increasing the dissolved oxygen content, .
Shunting will show cyanosis due to desaturated Hb and ruddiness due to increased Hb concentration due to chronic hypoxaemia
Describe the differences in vascular structure throughout the vascular system
The highest proportion of smooth muscle in the vessel walls is located in the small arteries and arterioles, while the postcapillary vessels have the smallest
The microcirculation is in intimate contact with the tissue it supplies
Describe the innervation of the vascular system
Sympathetic adrenergic nerves supply all vascular beds in the body. However, its extent varies widely, with arteries and arterioles directly innervated, and veins more sparsely (increasing with size), and no direct capillary innervation.
Parasympathetic cholinergic innervation of precapillary vessels exists in some organs.
How do the precapillary vessels change fluid extrusion/reabsorption?
The small arteries and arterioles are the site of the largest pressure change across the whole vasculature. Therefore they contribute the most to resistance
Vasodilation of these precapillary vessels reduces resistance and increases blood flow, and vice versa. Constriction means that energy dissipated as blood flows through the small arteries and arterioles is increased, resulting in a reduction in mean hydrostatic pressure.
Precapillary dilation leads to extrusion of fluid, and vice versa
What is local autoregulation of the vasculature and what does it do?
The organ has an intrinsic tendencey to maintain constant blood flow despite change in perfusion pressure
As perfusion pressure increases, there is an increase in blood flow that then returns to the previous level, often within a few seconds and vice versa.
This varies however- cutaneous circulation exhibits almost no autoregulation, while the cerebral circulation is tightly maintained
What is reactive hyperaemia?
After a short period of blood vessel occlusion, blood flow rises above the level of flow before the occlusion, for a period proportional to the duration of the occlusion
Describe myogenic control of the vasculature
An increase in transmural pressure on a blood vessel results in increased vascular contraction and vice versa
Responses of this nature are most potent in medium arterioles and small to medium veins. This is done as the pressure increase distends the vessel walls, depolarising the vascular smooth muscle cells and causing contraction
Describe metabolic control of the vasculature
Local vascular contraction is dependent on the perivascular concentration of metabolites. This is determined by the rate at which they are produced compared to the rate at which they are washed out.
More active cells produce more adenosine, etc, which stimulates contraction of nearby smooth muscle cells
How does the vascular endothelium achieve local control?
The endothelium releases nitric oxide, which acts on VSM to increase intracellular cGMP, causing relaxation.
It can also release endothelin, which causes Ca2+ channel agonism and vasoconstriction
How does noradrenaline act on vascular smooth muscle?
There are three options for its binding to the VSM membrane channels
- A1 receptors. This is linked to the G protein Gq, which activates phospholipase, increasing IP3 and DAG. This causes increased Ca2+ and vasocontstriction
- A2 receptors. These are linked to Gi proteins, which inhibit adenylate cyclase, decreasing cAMP, increasing Ca2+ extrusion and sequestering it intracellularly. This leads to vasodilation
What factors excite vs inhibit the release of NE from the nerve terminal?
Excitatory: Ang II, adrenaline
Inhibitory” ACh adenosine, dopamine, histamine, PGE1/2
Describe how cholinergic nerves act on the vasculature
Activation releases ACh, binding the the M3 receptors in vascular endothelium, stimulating NO synthesis. However, if it binds to M2, it causes vasodilation
Sympathetic cholinergic nerves are similar, but innervate precapillary vessels in skeletal muscles and sweat glands, leading to vasodilation and sweating
How does adrenaline vs noradrenaline affect the circulation?
NA causes widespread vasoconstriction excep for the coronary and cerebral circulations
A causes this as well as vasodilation in skeletal muscles and splanchnic circuits
This is done as B2 receptors (which stimulate cAMP to do vasodilation) have a higher affinity for adrenaline than noradrenaline. These receptors are located only in skeletal and splanchnic circuits
How do skeletal muscle vessels vasodilate during exertion?
At moderate and high exercise levels, sympathetic stimulation is ineffective, as the concentrations of extracellular metabolite become so high in the working tissue that they cause vasodilation as well as inhibiting sympathetic transmission
There may also be action of sympathetic nerves on B2 receptors
The metabolites don’t really affect postcapillary vessels
The speed and magnitude of hyperaemia is not totally explained by these mechanisms!
Describe how skin circulation is affected by changes in innervation
The skin has low capillary density and lots of shunting.
Blood flow at rest is even greater than requirements. only a receptors are present, and therefore is powerfully influenced by sympathetic innervation
Affinity of a receptors for NA decreases as skin temperature rising, leading directly to increased cutaneous blood flow
The sweat glands also activate the kinin cascade, increasing blood flow and improving heat loss
Describe how the cerebral curculation maintains its tight link to metabolism and blood flow
Total blood flow remains very constant, but regional variations may be marked. Perivascular pH and CO2, O2, K+ are used in matching the two. High PaCO2 causes increased flow and vice versa.
Catecholamines have little effect as they cannot penetrate the BBB. Sympathetic innervation provokes only transient results
Interstitial fluid volume and intracranial pressure can also cause alterations in flow- similarly to compartment syndrome
Describe reynaud’s disease
Associated with prolonged vasoconstriction of digital arteries of the hand when exposed to cold stimulus
Due to inappropriate responsiveness of a adrenergic receptors
In chronic disease, skin ulcers and bone necrosis may occur due to abnormal vessel structure
Describe how FEV1 changes as an asthmatic exercises and then rests
Initially it goes up, as sympathetic stimulation bronchodilates the airways
Then there is a massive drop in FEV1 as airway hyperresponsiveness causes histamine and leukotrine release, resulting in airway narrowing. This can be mediated by smooth muscle contraction or by increased thickening of mucus
Why does asthma present with a wheeze?
This occurs because when an asthma attack occurs, flow becomes proportional to elastic pressure over resistance.
The pleural pressure must increase as expiration is more and more forced, until the point at which pleural pressure equals the pressure within the airway- this then forces the airway to collapse, and expiration becomes effort independent as changing the force no longer increases the flow
Describe the interpretation of flow-volume curves
Flow is on the y axis, volume on the x axis
Expiratory flow sees the graph peak upwards sharply to PEF, and then decrease through FEV1 and to minimum. Inspiration has less flow peak, but just a curve underneath. Tidal breathing tends to be within the middle of this graph.
The first half of the Fexpiratory descent line is effort dependent, while the lower part is effort independent.
What is the difference between a healthy flow-volume curve and an unhealthy flow-volume curve?
A reduced PF
Reduced FEV1
Reduced FVC, but FEV1 reduced to a greater extent
Increase in residual volume
Tidal breathing occurs at higher lung volumes, esp in emphysema as it allows the airways to stretch, increasing use of elastic pressure to drive outflow
What are the advantages and disadvantages to using FEV1 and PEF as the measure of lung function?
FEV1: Much better for distinguishing abnormality and relatively effort independent
PEF is simple and cheap, but there is a wide normal range and it is relatively effort dependent.
Describe the area of the pressure-volume curve of breathing tidally and at high lung volumes, and its implication for pathology
Normally we breathe in the steep part of the sigmoidal pressure volume curve, but at high lung volumes this is flatter, indicating lower compliance. This means it takes more generation of pressure to maintain the same lung volumes in pathology
Describe why an inspiratory wheeze might occur?
Normally due to extrathoracic limitation, as both the elastic recoil must be overcome as well as the airflow limitation.
What causes inspiratory crackles?
Due to thickened interstitial barrier between alveloli capillaries- the basal airways close off during tidal breathing, and must be ‘popped’ open once the lung reaches a certain pressure. The noncompliant airways all open together, causing a crackle
Describe why shortness of breath is a common issue in COPD/ interstiatial lung disease
SOB mostly correlates with increased work of breathing, rather than actual hypoxaemia
Normally, tidal volume and pressure has an increasing slope. In fibrosis, this slope is flatter, meaning there is increased elastic work of breathing that needs to be overcome as the lung is less compliant. When exercising, this increases work of breathing markedly, so resp rate increases as it is easier to maintain adequate breathing in this way.
How does cardiac depolarisation move through the heart?
The wavefront spreads from endocardium to epicardium and from apex to base
It moves from SA node to atria, to AV node, to bundle branches to purkinje fibres
What features maintain sinus rhythm in the heart?
- Suppression of lower frequency pacemakers. While AV cells have an unstable membrane potential and could act as pacemakers, the SA node drives them because it has the fastest spontaneous rate. This suppresses the automaticity of lower pacemakers.
- Programmed excitation via the conduction system
- A prolonged refractory period in the myocardium
Describe how an arrhythmia may be generated
Arrhythmia is defined as any deviation from normal sinus rhythm.
It may be caused by early pacemaker discharge or activity triggered by an unstable RMP. This is caused by delayed or early afterdepolarisations. These tend to occur in the relative and supernormal refractory periods, though these are poorly conducted. Ectopic beats must be generated by numerous cells synchronously
It can also be due to impulse conduction, such as AV/bundle branch block (slowed heart rate) or reentry (altered time course of spatial or temporal repolarization)
Describe atrial flutter
Caused by a single atrial reentry circuit and assoc with fast atrial rate, increasing the likelihood of partial AV block
It shows sawtoothed waves between QRS complexes
Describe atrial fibrillation
Rapid disorganised atrial activation, with not all being conducted to ventricles and so causing a disordered ventricular rhythm. It is more common after lesions, CHF or in the elderly. Significant risk of clots and PE/Stroke
Describe ventricular tachycardia and fibrillation
Can occur in myocardial ischaemia, due to remodelling after healed infarction, heart failure or due to hereditary ion channel mutations. It is associated with rapid ventricular activation and impaired mechanical function
Describe the ionic currents that make up an action potential
Sodium and calcium are higher outside than within the cell, while potassium is higher intracellularly
When MP is brought to threshold, rapid transient openings of sodium channels carry the fast sodium current in and cause depolarization. This reduces the permeability of the potassium channel, preventing it at first from removing K+ ions. This depolarization also causes slow calcium channels to open, allowing Ca2+ in. this remains in balance for a plateau phase, before the K_ ion current increase due to fast and slow delayed rectifiers, returning levels to normal
Describe the activation and inactivation gates of the cardiac ion channels
These are gates that may be open or closed depending on the voltage status of the cell.
Eg. fast sodium channels have their gates shut at RMP, but open quickly with depolarization. Inactivation gates are open at rest, but shut as depolarization occurs. This means there is a brief delay between activation and inactivation, so allows a short transient sodium current, and is responsible for the prolonged refractory period of the AP. The gates progressively reset during repolarization
Describe how reentrant arrhythmia occurs
It is due to propagation of a current around a region in which activation is blocked due to refractoriness or injury. If only one side allows propogation, the wave will move around the region of block, and pass retrogradely up the other side. This means it is able to reactivate tissue and generate sustained activation around the entry circuit, if the time of propgation is the same as the effective refractory period of tissue (when reactivation cannot occur).
This means it requires a circuit, a unidirectional block, slow conduction or short ERP, and a trigger.
Vulnerability increases with decreased conduction velocity and refractory periods. In ventricular myocardium, this is most probably when repolarization is not spatially homogeneous
Describe WPW
The bundle of kent is present, proving an accessory pathway for propogation to move between atria and ventricles. Normally, the early activation collides with normal activation via the slower AV node current. This gives a wide QRS with slurred delta wave beginning, and short PR interval
It becomes an issue if ectopic activation occurs in the atria or ventricles which tissue in one of the pathways is refractory. This can cause rapid tachycardia, ventricular fibrillation and death
Describe why conduction velocity is important
The wavelength for a reentrant arrhythmia depends on conduction velocity and effective refractory period. Factors reducing the velocity increase the probability of this. It is influenced by cell dimension, gap junction density, and status of the membrane sodium channels
In the vulnerable period, the myocardium has a medium low MP, meaning few inactivation gates have rest- this means the number of sodium channels able to open is small, giving a slow depolarising current and non-uniform repolarization
What are the three main consequences for cardiac rhythm during ischaemia?
ATP decreases, so sodium potassium ATPase is inhibited, raising K+o and Na+i. This causes
- Slow conduction
- Reduced AP duration with nonuniform repolarization
- After-depolarizations
Describe how myocardial ischaemia causes slow conduction
Increased Extracellular potassium reduces the RMP, inactivating Na+ channels as the gates are partially closed already, and slowing conduction. Acidosis leads to decoupling of gap junctions, increasing electrical resistance and further reducing conduction velocity
Describe how myocardial ischaemia causes reduced AP duration and non-uniform repolarization
Kyperkalaemia reduces AP duration via the rectifier and the APT dependent currents. This reduces AP duration in the ischaemic region, leading to nonuniform current
Describe how ischaemia causes after depolarizations
The reduction of ATP means Ca2+i rises, and spontaneous release of oversoaded SR generates calcium transients, and increased extrusion of Ca2+ via the Na+/Ca2+ exchanger. This generates a depolarizing current. Typically these occur as DADs
Describe how MI may lead to VF
Onset of VT can cause positive feedback, where increased HR increases O2 demand and reduces diastolic perfusion. Increased HR can also impair ventricular performance further, increasing the extent of the ischaemic region and making VF more likely.
Tissue heterogeneity as a result can lead to disordered structure and electrical coupling, allowing a potential reentry arrhythmia to occur
Describe how cardiac rhythm is affected in heart failure
Cellular and structural changes occur, with dilated atria (increasing reentrant path length and stimulating stretch activated ion channels) .
It also causes atrial fibrosis, resulting in region dependent slowing of conduction
Changes in sodium calcium exchangers can also cause DADs and trigger reentrant arrhythmia
There is also remodelling of ANS inputs to the atria in a heterogeneous way, influencing its electrical properties
Similar processes occur in the ventricles
Describe LQTS
Ventricular arrhythmias that are triggered by exertion or emotional excitement, leading to fainting and sudden death
This is due to prolonged APDs, and generation of APs late in the plateau or early in repolarization.
EADs can result from prolonged APs, allowing Ca2+ channels to resent and reactivate. These channels are sensitive to adrenergic stimulation, explaining the reason for the occurrences.
Reentrant arrhythmia is a great risk due to increased non uniformity of repolarization
Describe the causes of LQTS
May be diet or drug induced
- Hypokalaemia
- Amiodarone (prolongs QT interval)
- Hereditary membrane ion channel issues
Describe the three common LQTS hereditary channelopathies
LQT1: Most common, due to mutation in delayed slow K+ rectifier channel, reducing repolarization and increasing APD
LQT2: Mutation of the rapid K+ rectifier channel, increasing APD
LQT3: Mutation in the sodium channel, causing failure to maintain INa inactivation later in the action potential. This allows late inward current, delaying repolarisation and increasing APD
Describe the ECG features of LQTS
A long QT interval
If VT results, it shows continuously varying polymorphic VT, named Torsade de Pointes.
It may resolve spontaneously or progress to VF
What are the equations for cardiac output and stroke volume?
CO = HR x SV SV = EDV - ESV
What overall factors affect ventricular performance?
Preload (Increased preload increases SV)
Afterload (Increased afterload decreases SV)
HR
Inotropic state
How does Calcium affect cardiac muscle contraction
Depolarization opens L type Ca2+ channels in the T tubules, allowing Ca2+ to enter the cell and bind to RyR2 receptors on the SR, opening calcium release channels. Therefore, Ca2+ conc rises rapidly in the cytoplasm.
Ca2+ then binds to regularatory protein TnC, allowing active sites on the thin filaments to be expose and allowing cross bridge formation.
How is Ca2+ removed from the cardiac cells?
SERCA pumps transfer Ca2+ into the SR, where it is stored.
Also some extrusion by Na/Ca exchangers
What factors affect inotropic state of the heart?
Magnitude and rate of SR calcium release
Affinity of TnC for Ca2+ ions
Describe the channels involved with Ca2+ release
The adenylate cyclase system is the most important
Gs stimulates adenylate cyclase, increasing cAMP, more protein kinase A and phosphorylation of L-type Ca2_ channels, phospholamban, ryanodine receptors and TnI. This leads to opening of L type calcium channels, SR stimulation, faster Ca2+ kinetics and faster X bridges
Therefore- faster Ca2+ release and reuptake, increasing inotropy
What does the SNS and PNS do in terms of Ca2+ release in cardiac function?
Noradrenaline and adrenaline act via B1 receptors to cause Gs activation
ACh from the PNS acts on M2 receptors, which activates Gi, which inhibits adenylate cyclase and increases K+ reuptake, shortening APs
Describe how force and length are related in cardiac contraction
There is both passive force and active force.
Passive force is related to the stretch acting on resting muscle, and active is that generated at a given sarcomere length.
Passive force limits sarcomere length to less that 2.4um
The force length relationship is much steeper in cardiac than in non cardiac contraction- this is due to the length dependent affinity of TnC for Ca2+
How does hypoxia affect the contractility of the heart?
If oxygen supply is reduced relative to demand, ATP stores quickly become depleted and pump operation is impaired.
Ca2+ in diastole is therefore elevatd, causing reduced relaxation, impacting electrical function and filling. Acidosis can also set in, impacting mechanical function as H+ competes with Ca2+ for TnC binding.
There is also increased extracellular K+, affecting AP duration, as the speed of depolarization is reduced.
Describe how myocyte orientation affects cardiac contractile function
Myocytes have a principal orientation, defined by the organization of collagen. When the heart beats, most of the pump function is performed by wall thickening, rather than any real change to the diameter of the heart.
How does the heart contract in space during normal systole?
- There is cifcumerential and longitudinal shortening, as well as wall thickening- changes are greatest endocardially
Circumferential shortening is greater than longitudinal.
Some torsion occurs as the apex twists counter-clockwise
Some shear deformations involve movement of cells relative to one another.
This is reversed in diastole
How does heart remodelling in heart disease affect cardiac geometry?
Myocyte hypertrophy and wall thickening
Increased LV collagen density and stiffness
Circumferential and longitudinal shortening decrease
EF is generally mainttained initially by increased torsion
Eventual enlargement of ventricular cavity ad reduction of ejection fraction
Where does cardiac innervation originate from?
Pre-ganglionic sympathetic fibres come from upper thoracic segments of the spinal cord, ascending in the paravertebral chain to synapse with postganglionic neurons in the sup, middle and stellate cervical ganglia.
Preganglionic vagal neurons come from the medulla oblongata and course down the neck and chest as branches of the vagus nerve.
Describe where the different nerves innervate the heart
Parasymp innervation of the SA and AV node, and atrial myocardium, is dense. The ventricles are less densely innervated
Sympathetic innervation is relatively homogenous
The right fibres innervate the SA, while the left do the AV node
How does sympathetic innervation regulate cardiac function?
Through norepi acting on B1 receptors in the myocardium. This causes phosphorylation of If, allowing more Ca2+ in and more reuptake into the SR to shorten AP duration
causes- increased rate
Reduced AP duration, so acceleration of impulse propagation through the AV node
Increased inotropic state
What happens if we stimulate the left vs right stellate ganglion?
Left- it predominantly innervates the AV node so we see less HR change but greater systolic pressure
If we stimulate the RHS it targets the SA node so we see a large change in HR but reduced systolic pressure change.
How does sympathetic stimulation alter the cardiac cycle
Pressure of atrial and LV contractions are increased
Initial blood ejection speed and max ejection speeds are greater
SV increases due to reduced ESV
Filling occurs faster, despite the reduction in diastolic interval
How does the parasympathetic nervous system alter the cardiac cycle?
Mediated by ACh, which binds to M2 receptors to turn off the Gs pathway, increasing K+ extrusion and reducing AP duration
It reduces HR
Also causes deceleration of impulse propagation through the AV node (and may cause block)
Compare and contrast the use of PNS vs SNS to regulate the heart
PNS stimulation is instant, SNS is slower, so respiratory sinus arrest is due to PNS stimulation/ this is because ACh has lots of sites and esterases, unlike epi/norepi
The PNS dominates short term heart rate control, and normally checks resting heart rate. When it’s active, the vagus is turned down
Describe how oxygen supply and demand affect the heart, and the factors that determine myocardial O2 consumption
Interruption to blood supply leads to decline in ventricular performance, with prolonged underperfusion leading to irreversible cell damage. Function is dependent on aerobic metabolism
Determinants include basal mechanism- the metabolic cost of maintaining organelle systems
Wall force development is related to pressure generated and dependent on the geometry of the ventricle- eg. a dilated heart requires more wall force development for a given LV pressure, both in terms of magnitude and time
Also inotropy and heart rate
What factors affect the heart’s oxygen supply?
Aortic pressure, extravascular compression (ie as the heart contracts the vessels get squished) and local regulation
This has impacts on perfusion pressure, impedance, and the need for CaO2, O2 extraction and vessel flow
MVO2 = Q x (CaO2 - CvO2)
Note that there is a capillary for each myocyte!
What determines coronary blood flow?
Coronary blood vessels are compressed during isovolumetric conraction, with some small recovery during systole. It then relaxes and allows full flow. Normally, Diastolic pressure time index should be greater than tension time index, but an loss of health can change this. Vascular resistance is mainly controlled by local factors
The SNS causes vasoconstriction of these vessels, resulting in vasoconstrictor tone under normal situations
It is often overridden by a concurrent increase in oxygen demand during times of stress.
What is the structure of the glomerulus?
The afferent blood supply goes to the glomerulus, which has the glomerular filtration basement- fenestrated endothelium, basement membrane and podocytes. Prourine is produced by fluid’s movement through these layers
What are the key roles of the kidneys?
Elimination of waste products
Control of fluid balance
Regulation of acid-base balance
Production of hormones
How does the kidney perform elimination of waste products?
The rate at which the blood is cleared is defined as the GFR, which is normally >120mL/min
What is the difference between AKI and CKD?
AKI is acute kidney injury, and occurs over hours to days
CKD is chronic kidney disease, and occurs over weeks, months or years. It is progressive but irreversible
Describe AKI and how it is staged
It can have multiple aetiologies, and is assoc with many preventable hospital deaths.
It is defined in 3 stages, with 3 being worse, and assoc with increased risk of death
What are the different types of AKI?
Pre renal
Renal
Post renal
How do you treat AKI?
Identify high risk patients and optimise their care
Stop nephrotoxic agents
Assess and optimise volume status
Monitor creatinine and urine output
What are some categories of patients ‘at risk’ of AKI?
CKD patients Those over 75 HF patients Liver disease CVD DM Polypharmacy
What are some medications that can be nephrotoxic?
NSAIDs
Gentamicin
Anti-hypertensive
Meds that are renally excreted should be revised
How do we assess volume status?
Check for dry mucous membranes
JVP
Oedema
Sunken eyes
What can we investigate in terms of AKI?
Strep serology Antibodies Hepatitis Coagulation Biopsy Ultrasound
How do you diagnose CKD
GFR will be very low- can be measured with Cr clearance or by clearance of injected substances eg. insulin, isotopes
What are some issues with using Cr clearance to determine GFR?
It is secreted in small amounts by the tubules, and so using creatinine tends to overestimate the GFR
Moderate and severe CKD also confounds the interpretation of creatinine clearance. As filtration decreases, extrarenal excretion of creatinine increases and muscle mass decreases, resulting in an overestimation in end-stage patients
What are the categories of GFR and Albumin staging?
5 stages for GFR going from >90, 60, 30, 15 and <15
Albuminuria has 3 stages of <30, <300 and >300
What can cause CKD?
Diabetic nephropathy
Glomerulonephritis
Hypertensive nephrosclerosis
PKD
What secondary factors does CKD engender?
Systemic hypertension Intraglomerular hypertension Glomerular hypertrophy Ca and P Dyslipidaemia Proteinuria Tubulo-interstitial fibrosis Toxicity of iron, ammonia and/or middle molecules
How does hypertension interact with CKD?
Progression of CKD is linked to HT, and lowering it can slow the speed of progression
How does proteinuria affect CKD and how can it be modified?
It’s important for prognostics. Reducing proteinuria improves outcomes
It can be modified with weight loss, ACEi/ARB, statins, moderate protein restrictions, alowering BP
How are calcium and phosphate implicated in kidney disease?
Ca and P content of the kidney is increased in CDK, assoc with progressive decline in renal function. it gets deposited within the kidney, but its reduction can be assoc with reduction in rate of decline
This is managed by limiting dietary phosphate, or giving phosphate binders so that phosphate is not absorbed.
How does water balance change in CKD?
CDK patients are more prone to either dehydration or volume overload.
What other aspects of the kidney are affected in CKD?
Reduced EPO, vitamin D, RAA etc
Issues with Na, P regulation
Typically develops metabolic acidosis due to lack of non-organic acid excretion- may need to add oral sodium bicarbonate
Describe uraemia
Manifestation of organ dysfunction typically seen in CDK 4/5
No single compound is solely responsible
How does uraemia affect the different body systems?
Neuro- fatigue, sleep, headache, seizures, paralysis
Haem- anaemia, easy bleeding, platelet dysfunction, infection
CV- pericarditis, HT, HF, IHD, PVD
Pulmonary- Pleuritis, uraemic lung
GI- anorexia, N&V, bleeds
Metabolic- glucose intolerance, hyperlipidaemia, malnutrition, sex dysfunction, infertility, osteodysplasia
Skin- pigmentation, easy bruising, uraemic frost, pruritis
Psych- depression, anxiety, denial, psychosis
How do you manage uraemia?
Treat the primary disease, secondary factors
Avoid nephrotoxins
Correct abnormalities
Renal replacement therapy
How do you treat end stage kidney disease?
Conservatively if not indicated for other treatment
Dialysis (can be peritoneal or haemodialysis)
Renal transplant (can be cadaveric or living)
Describe the RAAS pathway
Activated by SNS activity, low BP or low Na/K+ passing the JG cells
Causes vasoconstriction, formation of angII, and secretion of aldosterone.
What does the RAAS system do to worsen conditions?
It can increase activity is CCF and hypertension as it works in harmony with the SNS
It’s involved with CHF progression
Can have adverse CV effects including hypertrophy, atherosclerosis development, and pro-inflammatory conditions
Where do agents acting on the RAAS have their effect?
ACEs act on angiotensin converting enzyme, which changes Ang 1 to Ang2. However, blocking this also breaks down bradykinin and increases levels of Ang9 and heptopeptide concentrations increase. This means it has multiple benefits for blood vessels.
However, other pathways can be used instead, to increase Ang II over time
Ang II antagonists- inhibit angiotensin II type 1 receptors
Where does angiotensin II act?
Phospholipase C GPCRs
What are the different ang receptors and what do they do?
Type I receptors- affect the kidney, heart, VSM, Brain, adrenal glands, adipocytes and placenta. Main target of ARBs
Type II receptors- affect the heart, adrenals, CNS, kidneys Also counterbalance some type I effects and cause cell proliferation & apoptosis. These are allowed to exert their beneficial effects when type I receptors are blocked
What are the pathophysiological effects of angiotensin II?
Cardiac myocytes: Cause hypertrophy, apoptosis, cell sliding, wall stress, increased O2 consumption and impaired relaxation
Fibrobasts: Cause hyperplasia, collagen synthesis and fibrosis
Peripheral artery: Cause vasoconstriction, endothelial dysfunction, hypertrophy and decreased compliance
Coronary artery: Cause vasoconstriction, endothelial dysfunction atherosclerosis, and thrombosis.
What does aldosterone do?
Causes hypertrophy and Ne in cardiac myocytes
Hyperplasia, collagen synthesis, fibrosis in fibroblasts
Vasocnstriction, endothelial dysfunction, hypertrophy and decreased compliance in peripheral arteries
Potassium loss and sodium retention in the kidney
What are the benefits of ACEi initially and a few weeks later?
Benefits are reduced ang II concentration, reduced aldosterone concentration, and potentially increased Ang 9. Also, bradykinin levels rise, causing vasorelaxation and increased endothelial function
However, eventually aII and also begin to increase, due to chymase activity
What are the drug names used in RAAS, and their pharmacokinetics?
Ace inhibitors are most common, especially cilazapril. All others end in ‘pril’
ARBs include candesartan. All others end in sartan
ACEs are given as prodrugs and hydrolysed int he liver. They are excreted mostly renally
ARBs have variable excretion
What do ACEis and ARBs do?
They cause vasodilation, lowering arterial and venous pressure, and reducing preload and afterload
They decrease blood volume, causing natriuresis an diuresis.
Decrease sympathetic activity
Decrease cardiac and vascular hypertrophy
What are the indications for ACEis and ARBs?
ACEs: Hypertension, either monotheraphy or combination with a diuretic
Also CCF as part of multiple treatments with a diuretic, B blocker or aldosterone antagonist
ARBs: Used in ACE inhibitor intolerant patients, hypertension and heart failure
NEVER USE THE TWO TOGETHER
What are the side effects from ACEis and ARBs?
ACE: Produce a dry cough due to bradykinin increases, as well as hyperkalaemia, decreasd renal function (initial), hypotension and angioedema due to vasodilation
ARBs show dry cough in small amount of people, hyperkalaemia, renal deterioration, hypotension and angioedema, though less than ACEis
They are both contraindicated in pregnancy
When do we need to be careful when using ACEis and ARBs?
In hyperkalemic patients
Renally impaired patients
Volume depeted or diurised patients, as they are dependent on RAAS to overcome their dehydration
What are absolute contraindications in the use of ARBs and ACEIs?
Pregnancy
Bilateral renal artery stenosis, as they have narrowing proximal to the glomerulus
They need ang II to constrict the efferent arteriole to maintain glomerular pressure.
If it is not present, it can reduce perfusion across the glomerulus and cause AKI. Therefore, you need to watch creatinine for the first few weeks when going on the drug.
What are some future direction in ARBs and ACEis?
Can get renin inhibitors potentially
Also vasopeptidase inhibitors which block the breakdown of ‘good’ things like bradykinin and substance P.
What are the functions of alpha receptors?
A1 (post-synaptic): They cause vasoconstriction and increase BP (A1a in the prostate)
A2 (pre and post synaptic): Inhibit release of norepi and insulin
What do alpha blockers do?
They act on alpha 1 receptors to block noradrenaline landing (alpha 2 antagonism isn’t used clinically)
What are some examples of alpha blockers?
Doxazosin- blocks all a1 subtypes for causing vasodilation
Tamsulosin- specific to a1a so useful for prostatic profile but with little effect on BP
What are some indications of alpha blocker use?
Essential hypertension. However, they don’t tend to be first- line therapy and are used in combination with diuretics and ace inhibitors to acheive targets.
Also useful for prostatism as they improve tone of vessels can can reduce symptoms.
They can also be used to block norepi effects postoperatively
Describe doxazosin
A reversible alpha blocker with greater affinity for 1 than 2
Blocks all a1 subtypes for vasodilation
It can also reduce prostatic symptoms
Given once daily, starting with a low dose and titrating uo
What are the adverse effects of alpha blockers?
Orthostatic hypotension causing dizziness- can just give the first dose at night Feeling tired Nasal stuffiness Dry mouth Urinary incontinence in women
Describe phenoxybenzamine
Irreversible alpha blocker used in phaeocrhomocytoma (eg. for sympathetic tumours) or preoperatively
Gives postural hypotension, tachycardia, nasal stuffiness and CNS symptoms
What are some combined alpha and beta blockers?
Lebetalol- used in pregnant women hypertension
Carvedilol- used in CCF
These are B1 = B2 > a1 >a2
Describe tamulosin
An oral alpha blocker than blocks a1a receptors,causing a relief from prostatism and less postural hypertension
What are the indications for calcium channel blockers?
Hypertension, angina, arrhythmias and vasospasm
This is because it causes vasodilation, reduced cardiac work, affect supraventricular tachyarrhythmias (good for AF)
How do calcium channel blockers work and what do they do in the heart and vessels?
They block voltage-operated L type Ca2+ channels in cardiac tissue and smooth muscle. They do have some selectivity for resistance vessels, the myocardium, and conducting tissue.
In vascular smooth muscle, they decrease arteriolar tone, PVR, BP and afterload
In cardiac cells they decrease contractility, sinus node rate and AV node transmission
Describe some calcium channel blockers and their side effects
Dihydropyridines like Nifedipine and Amlodipine. These affect resistance vessels with little cardiac effect, causing flushing, headache and oedema
Phanylalkylamines like verapamil act on cardiac tissue to cause heart block, negative inotropy and constipation- so they’re not for heart failure
Bezothiazepines like diltiazem are in the middle of both
What are the pharmacokinetics of CCBs?
They are all oral but can be made IV
They have significant first pass metabolism with CYP450
They have a variable half life but those with short T1/2 may come in slow release capsules
Describe nifedipine
Used for hypertension and vasospasm
Main side effect is oedema, probably due to precapillary arteriole relaxation and potential block of lymphatic peristalsis
This type of oedema is resistant to diuretics
Describe diltiazem
Used for angina, hypertension and tachyarrhythmias
Can be used with beta blockers as it isn’t the most potent B blocker
Describe verapamil
Used for tachyarrhythmias and hypertension. Can cause bradycardia and negative inotrope
Never used with beta blockers, and needs care with statins
What are the adverse effects of CCBs?
Flushing
Headache
Oedema
Negatively inotropic and constipation (verapamil)
What would you give a man who has stable angina, aspirin and high BP?
You would use diltiazem
Normally you would use a B blocker, but this is contraindicated by asthma
What would you use for a 56yo with hypertension and increased lipids?
Diretuc, ACEi, and a vasodilator as well as a statin
Give a general overview of alpha blockers and calcium channel blockers:
Alpha blockers: 3rd line for hypertensio, used in combo with ACEis and diuretics. Consider if concurrent prostatism
CCB: 2nd or 3rd line for hypertension. Combined with ACEis and diuretics. Use if concurrent angina, for rate control and SVT control
What are the indications for beta blockers?
Hypertension
Angina, as they reduce cardiac work
Heart failure
Arrhythmias, as they are god for AF and SVT as they block reentry currents
What are the actions of B receptors?
B1 cause tachycardia, vasoconstriction and renin release
B2 cause bronchorelaxation and renin release
Therefore blocking them can reduce heart rate and contractility, but can have an adverse effect for asthmatics
How do B blockers work
They change beta adrenergic receptor kinases to decrease cAMP
They vary in their selectivity
Metoprolol has much more B1 sensitivity than B2, while propanolol has similar between the two.
Mixed antagonists between a and b are the ones indicated in pregnancy
What are some differences between B blockers?
Selectivity
Elimination may be renal or liver
Half life
Water soluble (excreted renally, long T1/2, caution with impaired renal Fx)
Lipid soluble (liver excreted, rapid absorption and metabolism, short T1/2 but cross BBB)
What are the pharmacokinetics of B blockers?
They are well absorbed orally
Can come in sustained release forms (esp liver solubles)
They also have some iv preparations
(Esmolol is only given IV as it is rapidly absorbed by plasma esterases (only for ICU patients, eg in aortic dissection)
What are the effects of B blockers?
BP lowering through unclear mechanisms Less HR and decreased cardiac work Reduced renin and SNS activity Reduce Norepi release Negative chronotropy at SA and AV nodes Negative inotropy in the short term, but positive in the long term Thyrotoxicosis Reduced aqueous humour production Decreased glycogenolysis (can reduce gypoglycaemic symptoms in diabetics making it more dangerous)
What are some adverse effects of B blockers?
Asthma exacerbation
Hypotension, bradycardia and acute CCF exacerbation due to negative inotropy
Incometence
nightmares
masking of hypoglycaemia
Drug withdrawal as long term post synaptic receptors go up- if stopped immediately, see tachycardia, sweating, angina
What are some cautions for prescribing B blockers?
Verapamil is a contraindication as there is negative chronotropy there too, increasing risk of heart block
Diltiazem is acceptable
Other BP lowering drugs
Diabetics
What are some indications for B blocker usage?
Angina
Most MI to decrease arrhythmia, ventricular rupture and cardiac remodelling
Heart failure
How does receptor frequency change in a healthy vs damaged heart?
Normally there is mainly B1, with some B2 and a little A1
In a failing heart, this changes to 50% B1, 25% B2 and 25% A1
How do B blockers help in heart failure?
Decrease HR and O2 consumption, Increase filling Upregulate B receptors Attenuate apoptosis Improve baroreceptor functioning Improve LV remodelling
How do B blockers help in hypertension
Mechanism unclear but used in 2nd or 3rd line therapy
What med would you use for a 70yo with SOB, pulmonary oedema, hypoxia, fluid overload and chest crackles
Initially: Diuretics, O2, ACEi
LOW DOSE B blocker due to not wanting to slow heart further
Titrate up when his condition is stable
What med would you give for a 60yo anxious hypertensive on bendrofluazide and cilazapril with high BP? What warning would you give?
Add a B blocker once daily for ‘anxiety’ and HR
Warn about fatigue, dizziness, erectile dysfunction
Enquire about asthma
What is the definition of an inotrope?
A drug that changes the force of cardiac muscle contraction- can be positive or negative
What is shock and what are the different categories?
Shock is characterised by inadequate organ perfusion to meet the tissue’s O2 demand, leading to organ dysfunction
Can be hypovolemic- due to haemorrhage or dehydration
Cardiogenic- HF
Distributive- sepsis or anaphylaxis
Obstructive- tamponade, PE
How are inotropic drugs given and why?
Tend to be given via continuous infusion into a large vein
This is because peripheral drugs may take some time to deliver drugs centrally, and may risk phlebitis due to toxicity
What are the goals and risks of shock>
Goal is to restore BP and ensure euvolaemia
Normalise systemic perfusion to preserve organ function, and then treat the underlying cause
Shock has a high risk of death
Describe the causes and consequences of cardiogenic shock
Caused by ischaemic disease, valve dysfunction, acute VSD
Shows high systemic resistance due to symp activity, and low cardiac output
How can you treat cardiogenic shock?
The goal is to get preload as high as ideal as possible depending on the inotropy.
Inotropic agents can be used to return the heart to normal, augmenting contractility after preload has been established, improving cardiac output and global perfusion
HOWEVER they do increase the risk of tachycardia, MI, arrhythmia, and increase myocardial oxygen consumption
What are inotropic agents/vasopressors?
Alpha and beta adrenoreceptor agonists to increase tone, vasoconstriction, and cardiac contractility Include Norepi Epi Dobutamine Dopamine
Describe dobutamine as an inotropic agent
It is a very pure B agonist, but can cause vasodilation
Positive inotrope but variable chronotrope
Caution in hypotension as may worsen it or precipitate tachycardia
Describe Noradrenaline as an inotropic agent
First choice vasopressor as it’s a potent a agonist
Minimal B adrenergic effects so little inotropy and chronotropy
Causes increased PVR and BP
Short T1/2 due to reuptake by uptake I channels at nerve terminals
Describe adrenaline as an inotropic agent
Mixed A and B agonist depending on whether an organ has more alpha or beta receptors. Can vasoconstrict and vasodilate
Potent inotrope and chronotrope so used in cardiac arrest
Increased myocardial O2 consumption
Retaken up by postsynaptic cells at uptake 2 channels so needs continuous IV infusion
Useful in anaphylaxis as causes BP increase and dilates bronchi
Describe dopamine as an inotropic agent
Precursor of norepi Taken up by uptake 1 and 2 so short T1/2 Given low dose, can cause increased renal blood flow At moderate doses it shows B effects At high doses it shows a effects
What are some side effects of inotropic drugs?
Sympathetic activity is already high in shock
Shows vasoconstriction, potentially causing ischaemia in the heart, limbs, gut or brain
Increases cardiac work, potentially causing cardiac work and ischaemia
What are phosphodiesterase inhibitors?
Amrinone/Milrinone
They cause vasodilation and positive inotropy by preventing cAMP breakdown by phosphodiesterase III
They are often added to dobutamine in intensive care settings
What are some side effects of phosphodiesterase inhibitors?
Thrombocytopenia
Hypotension
Arrhythmias due to increased cAMP
Mortality
What are calcium sensitisers?
Levosimendan
- Enhances Tn sensitivity to Ca2+ to increase inotropy
Can cause arrhythmia or death
Describe the indication for digoxin
Atrial fibrillation and rate control as it slows HR, improves cardiac work and can help in acute or chronic heart failure
Has no effect on mortality, but reduces symptoms and hospital admissions
What is the pharmacokinetics of digoxin?
1.6 day T1/2 so needs a loading dose for quick effects
Kidney elimination so care in renal patients
What is the mechanism of action for digoxin?
Blocks Na+ extrusion so that Na+ rises
To compensate, a sodium/calcium exchanger activates, bringing more Ca2+ into the cell. But this is dangerous in hypokalemic patients as it can exacerbate digoxin toxicity as it binds competitively with the receptor
It also augments vagal tone at the AV node, slowing AV conduction and ventricular rate
What is digoxin used for clinically>
Acute heart failure with fast AF
Third line for rate control behind B blockers and diltiazem
What are the symptoms of digoxin toxicity?
Arrhythmias ECG changes (increased PR interval, LQTS, reverse tick sign during the ST segment) NV Abdo pain Fatigue Visual complaints Muscular weakness Dizziness
What are some interaction of digoxin?
Hypokalemic patients increase digoxin effect side effects so care must be taken when given to a diuresed patient
Also interacts with Quinidine, amiodarone, verapamil, diltiazem etc, resulting in increased plasma levels
PGP inhibitors also reduce its excretion
What is essential hypertension?
Blood pressure above 140/90- mainly used for trials
Why is hypertension an issue?
It’s a major risk factor for stroke, coronary artery disease and renal disease
CVS death risk doubles for ever 20mmHg systolic and 10mmHg diastolic
It is common, esp over 65, but poorly diagnosed and treated, esp in developing countries
How does treatment of hypertension help?
Reduction in stroke, MI and mortality
How can you treat hypertension?
Lifestyle changes, including diet (esp sodium), weight loss, exercise and alcohol reduction
Drug therapy- mainly polypharmacy
What are issues with treating hypertension?
It’s a lifelong condition, assoc with concurrent disease, and often asymptomatic
Therapy must be daily, and has side effects
What are the drugs used to treat hypertension?
Think ABCD Ace inhibitors/ARBs (first line) Beta blockers Calcium channel blockers Diuretics
Describe thiazide diuretics
Includes bendrofluazide, etc.
Inhibits Na/Cl exchanger in DCT to decrease BP. They can also vasodilate as they open vascular K+ channels
While plasma volume and CO return to normal after about a week due to the activation of RAAS, BP doesn’t increase due to the action on blood vessels
What are some side effects of thiazide diuretics?
Increase glucose, reducing tolerance Increase urate, precipitating gout Decrease potassium, sodium, MG++ Diuresis Erectile dysfunction
Describe loop diuretics
Frusemide
Inhibits Na+/K+/Cl- cotransporter in the aschending LoH
Potent diuretic with little antihypertensive effect alone
Can cause dehydration and polyuria
Used with ACEi for potent effect
Describe potassium sparing diuretics
Spironolactone (aldosterone antagonist)
Inhibits distal Na+/C+ exchange
Can cause hyperkalaemia as it blocks K+ wasting
Used for people with resitant hypertension
What are miscellaneous antihypertensive agents?
Vasodilators like minoxidil that open K+ channels
Ones that act on the medulla to decrease sympathetic tone like methyldopa ad clonidine
What are common drug combinations in the treatment of hypertension?
Younger patients: Start with A or B
Older: Start with C or D.
(This is because young people have high renin hypertension whereas older people have low renin hypertension)
Then: Add an A/B or C/D (whatever is opposite)
Then: A or B + C AND D
Then: Add alpha blocker, spirolactone or other diuretic
What is an appropriate drug for hypertension with heart failure
ACEi or diuretics
What is an appropriate drug for hypertension with angina/heart failure?
B blocker
What is an appropriate drug for hypertension with prostatism
Alpha blocker
Describe hypertension in pregnancy
Can cause maternal and fetal complications, like abruption, IUGR and prematurity Can give central agents Labetalol Ca channel blockers Vasodilators STAY AWAY FROM ACEi Diuretics Atenolol
What is a polypill
One pill with small doses of all classes of hypertensive medication (ABCD)
All are sub-therapeutic so don’t tend to give side effects, but they act synergistically to have a good effect
Where are the different fluid compartments and what is their composition like?
Intracellular fluid within cell membranes
Extracellular fluid outside of cell membranes
- Can be interstitial- found in the interstices, and the medium between which molecules travel between the ICF and intravascular space
- Can be transcellular- formed from transportation activities of cells. Includes CSF, joint fluid, pericardial fluid.
ECF: High sodium, low K
ICF: Low sodium, high K
Maintained by the na/K ATPase
How is water and salt of the body controlled?
Occurs in the kidney. GFR is approx 120mL.min
The proximal tubule reabsorbs 2/3-3/4 of the salt and water
The LoH reabsorbs water across the descending loop, and ascending loop reabsorbs 15-20% of sodium.
Some sodium is reabsorbed in the DCT and CD
Describe how ADH acts
It is produced in the hypothalamus and released from the post pituitary when BP falls or osmolarity increases.
It causes increased reabsorption of water to increase BP and reduce osmolarity
Describe how aldosterone acts
It is a mineralocorticoid stimulated by high potassium or Ang II
It acts on the DCT and CD to increase sodium reabsorption and potassium excretion
Describe the causes of hypernatremia
Impaired thirst or consciousness No water access Burns Diarrhoea Blood loss Solute diuresis- HONK, DKA, drug overdose
Describe diabetes insipidus
A reduction in the amount or efficacy of ADH (central or nephrogenic)
Presents with polyuria and water loss, with dilute urine
Patient can’t drink enough to keep up with losses, showing elevated plasma osmolality, hypernatremia and dehydration
What can cause central vs nephrogenic diabetes insipidus?
Central: Pituitary not producing enough ADH due to brain injury etc
Nephrogenic: Genetic issue with aquaporin channels, with partial or complete ADH resistance
What is solute (osmotic) diuresis?
Increased solutes in the tubules that cannot be reabsorbed causing increased urination
When drinking can’t keep up it leads to dehydration
What can cause hyponatremia?
Excessive sodium loss or excessive water retention (or both)
Describe pseudyhyponatremia
Presents with normal serum osmolarity as some other solute may be making the ICF volume higher
For example, hyperglycaemia causes water to move into the ECF
How do we determine the causes of hyponatremia?
Check urine osmolarity
If low- consistent with water intoxication, psychotropic drugs
Check volume status of patient
- Hypovolemia- dehydration, with sodium loss but relatively less water loss. Due to diarrhoea, vomiting, bowel obstruction, burn, sweating, diuresis, addison’s disease, ketonuria, osmotic diuresis or RTA
Hypervolemia- fluid overload, with sodium retention but relatively more water retention. Due to cirrhosis or nephrotic syndrome
Euvolaemic- due to SIADH, endocrinopathies like hypothyroid or low cortisol.
What is SIADH?
Inappropriate ADH is produced in the absence of normal stimuli such as a low BP. The body accumulates too much water, but this is stored in cells to the patient doesn’t appear overloaded. Urine osmolality isn’t low, and neither is urine sodium. Causes can be trauma, surgery, tumours, chronic lung disease or head injury
What are the symptoms of hyponatremia?
If slow onset- brain may adapt, so just confusion and ‘not being themselves’
If rapid onset- cerebral oedema leads to confusion, seizures and coma, requiring more vigorous treatment
How should we be cautious in treatment of hyponatremia?
If it is treated too quickly, it can cause central pontine myelinosis. This compresses myelin sheaths, causing spastic paralysis, quadraparesis, pseudobulbar palsy and irreversible locked-in syndrome
How is hyponatremia treated?
If slow onset: Generally just fluid restriction
If fast onset- normal saline slowly in the ICU
Where do different renal drugs act?
Carbonic anhydrase inhibitors- PCT
Loop diuretics- LOH
Thiazide diuretics- DCT
K+ sparing diuretics- CD
What does magnesium do, and where is it stored?
It has a role in bone formation
Co-factor in enzymatic reactions like ATP metabolism, muscle contraction/relaxation, normal neurological function, release of neurotransmitters
Regulation of vascular tone
Cardiac rhythm
Platelet-activated thrombosis
Stored in bone, muscle and soft tissue. Only 1% is extracellular
When dissolved, it attracts water molecules, expanding its physical volume (active transport required to carry it across membranes)
How are body magnesium levels controlled?
Mainly by the kidney
Some is reabsorbed in the PCT by the paracellular pathway
Most is reabsorbed in the thick ascending limb of the LoH, moving paracellularly with Claudin 16/19 channel
There is active reabsorption in the DCT
What can happen if there are mutations in the channels that reabsorb magnesium?
Hypermagnesurea, and hypomagnesaemia with potential stone formation
Assessment by serum Mg, red cell Mg, 24h excretion, Mg retention test and isotope analysis
Total body Mg can be low even if serum Mg is normal
What are the causes and consequences of hypomagnesaemia?
Due to decreased dietary intake, GI malabsorption, diabetes, hyperaldosteronism, SIADH or renal loss (congenital, acuired or drug induced by aminoglycosides, amphotericin, omeprazole)
Symptoms include weakness, fatigue, fasciculations, cramps, tetany, numbness, paraesthesia, seizures and arrhythmia
Treated with oral or IV Mg
Describe hypermagnesaemia
Hypermagnesaemia can be due to advanced CKD as compensatory mechanisms may be inadequate (or drug induced)
Shows weakness, N&V, impaired breathing, heart arrhythmias
Describe how potassium is found in the body
Mainly comes from fruit and vegetables. It has a high intracellular concentration and a low extracellular concentration
How is the level of potassium in the body controlled?
Immediate buffering occurs regulated by insulin (hyperglycaemia leads to K+ efflux from cell in exchange for glucose, causing hyperkalaemia)
Acidosis can drive K+ in a similar away
How do the kidneys control K+ levels?
K+ filters freely across the GBM, mainly reabsorbed by Na/K ATPase in the PCD, with some paracellular movement
In the LoH it is absorbed by ROMK channels, the Na/K/Cl pump, and the Na/K pump
Aldosterone regulates collecting tubule action
What are the symptoms of hypokalaemia?
Muscle weakness Paralysis Cardiac conduction abnormalities Cramps Constipation
Describe hypokalaemic periodic paralysis
Mutation of K+ channels on cell membranes, triggered by high carb meals (insulin) or SNS activation causing periodic weakness
What can be responsible for losses of potassium?
Renal losses
- Aldosterone based, eg a tumour. Conns syndrome has an adrenal adenoma secreting aldosterone, presenting with hypokalaemia and hypertension
- Licuorice
- Diuretics
Gut losses
- K+ loss from diarrhoea or vomit
Treated by treating underlying condition and replacing K+ orally or IV if severe
What are the symptoms of hyperkalaemia and why is this important?
Fatigue Weakness Paraesthesia N&V Dyspnoea Palpitations Emergency as it causes PR prolongation, wide QRS and peaked T waves Can cause cardiac arrest and VF
What can cause hyperkalaemia?
Addison’s disease
Increased intake
Disruption of cell intake (B blockers, acidosis, rhabdomyolysis)
Decreased excretion- renal failure, hypoaldosteronism, ACEis/ARBs
Pseudohyperkalaemia- due to a haemolysed blood sample due to blood cells being left long enough (give repeat test and ECG)
What is addison’s disease?
Decreased cortisol and aldosterone secretion, with high K+, low BP, weight loss, lethargy, and pigmentation due to excessive ACTH that crosses onto melanocytes
Diagnosed on short synacthen test
Treated with adrenal replacement
How do we treat kyperkalaemia?
- Stabilization of AP with Ca2+
- B agonists and Insulin push K+ into cells, but give glucose concurrently
Treat acidosis with oral/IV bicarbonate
Reduce absorption with cation exchange products, binding to K+ in the gut and increasing fecal elimination
Increased renal elimination with dialysis or a K+ wasting diuretic (Fruzemide)
What are the nervous efferents that affect the cardiovascular system?
The sympathetic and parasympathetic outflow from the ANS to the heart and blood vessels
Components of the neuroendocrine system, including catecholamines, from adrenal medulla, RAAS, ADH and natriuretic peptides
What are the nervous afferents that carry information to the cardiovascular system?
Mechanoreceptors in the walls of blood vessels or cardiac chambers- contain stretch sensitive ion channels, and are activated by distension. Activation is therefore dependent on transmural pressure and the distensibility of the chamber in question
Describe the systemic arterial baroreceptors
These are found in the carotid sinus (CNIX) and aortic arch (CNX). They give rise to myelinated and unmyelinated afferents, and also receive efferent innervation.
Their threshold for activity is 30-50mmHg, and saturation is 150-180mmHg.
Rate of firing is greater for pulsatile pressure than for steady pressure, even if the mean pressure is the same.
They are also adaptive- if sustained high pressure occurs, they will fall back to control levels after a few hours to days. This is because they become less sensitive after activation.
What affects the firing of the central baroreceptors?
It is affected by pressure, as well as being modulated by external neural factors and local paracrine effects
NO and prostacyclin also increase baroreceptor sensitivity, while endothelin reduces it.
What is the effect of changes to firing of baroreceptors?
When arterial pressure falls, baroreceptors decrease their firing, resulting in augmented sympathetic outflow to the heart and vessels, reduced cardiac vagal activity, and increased catecholamine secretion from the adrenal muscle.
This causes increased HR and inotropy, and constriction of precapillary sphincters
And vice versa.
Additionally, it causes changes in metabolism of ADH (and ang II more slowly)
Describe the cardiac receptors of the cardiovascular system
Cardiac receptors have myelinated vagal afferents
They are located in subendocardial tissue, mainly in the veno-atrial junctions. The atrial receptors are sensitive to the filling of highly compliant antrial chambers. The receptors emit bursts of firing synchronous with atrial contraction (a wave) or ate in ventricular systole, when atrial filling is most complete (v wave)
They function to provide afferent information on the extent of cardiac filling
They are directly influenced by changes in venous return and blood volume- considered to be low pressure/volume receptors
Describe the unmyelinated component of cardiac receptors
Unmyelinated C fibre afferents have greater density than the myelinated ones. Their output increases markedly when cardiac filling goes up. This causes reduced sympathetic outlfow to the heart and vessels, increased vagal activity, reduced catecholamine secretion, and decreased ADH and AngII
Describe the osmoreceptors?
They are found in the supraoptic and paraventircular nuclei of the hypothalamus. They are stretch sensitive cells that detect changes in effective plasma osmolality by altering their volume
They increase secretion and release of ADH in response to high plasma osmolality, and vice versa
Describe the chemoreceptors?
There are peripheral chemoreceptors in the aortic and carotid bodies, and there are central chemoreceptors in the hindbrain
They respond to increased PaCO2 and H+, and reduced levels of PaO2. For the peripheral chemoreceptors, the latter response is the most important.
Increased discharge of peripheral chemoreceptors (due to reduced paO2, stimulates increased sympathetic drive to heart and blood vessels.
This can cause some patients to be resistant to blood pressure drugs.
How is the CV system controlled within the brainstem?
There are discrete groups of neurons in the ventrolateral medulla oblongata that are responsible for the tonic activity and reflex control of the autonomic nerves supplying the heart and vessels
Preganglionic sympathetic neurons in the intermediolateral column of the thoracic spinal cord are the common pathway for sympathetic heart drive. Their activity is driven by cell bodies in the rostral ventrolateral medulla (RVLM) (stroke here causes poor BP control)
Another neuron pool in the ventrolateral medula called the caudal ventrolateral medulla inhibits the RVLM activity
The nucleus tractus solitarius is the initial processing and relay centre for sensory info from systemic arterial baroreceptors and cardiac/respiratory receptors
Afferents enter the hindbrain in nerves IX and X, and synapse within the NTS. This is relayed to regions in the ventrolateral medulla for CV control
Cardiac vagal nuclei (CVN) is the centre for cardiac parasympathetic vagal activity
How do the brainstem CV areas communicate?
Excitatory connections between NTS and CVN and NTS and CVLM
Inhibitory between CVLM and RVLM
Excitatory connection between RVLM and preganglionic sympathetic neurons
How do we lose and gain fluid and electrolytes?
Lost by sweating, diuresis, diarrhoea, blood loss, vomiting
Gained through diet
What is the difference in diffusion between Plasma/ISF and ECF/ICF?
There is a porous membrane between the plasma and ISF, so fluid and electrolyte are able to freely diffuse, with proteins being held back to form a pressure gradient
The ISF/ECF barrier is fairly solid, so only H2O is able to diffuse freely
What determines water movement across cell membrabes?
Osmotic gradients and hydrostatic pressure
Net water movement: K[Pc-Pt]-[Opl-Oif]
What happens if isotonic fluid is added to the ECF?
ICF volume will not alter, but plasma volume will increase. This increases blood volume, filling pressure of the heart, and cardiac output. If TPR is unchanged, this also increases BP.
What happens if hypotonic fluid is added to the ECF?
This will reduce the osmolality of the ECF, causing water to flow into the ECF. At equilibrium, the volumes of both compartments will be increased
How does plasma ADH change in response to varying osmolalities?
It tends to stay low until the threshold, when it increases linearly. However, after it reaches a max effective conc it increases in concentration, but has no further physiological increase
Give the activity pathway for cardiovascular receptor firing.
Decreased intrathoracic blood volume causes reduced cardiothoracic receptor firing, causing an increase in ADH quickly, stimulating thirst and water retention
It also causes a slightly slower increase in sympathetic activity, and RAAS, causing sodium retention, and reduced capillary bed filtration pressure. This causes water to move from the ISF to plasma, called an internal transfusion
How do red cells and other blood components get replaced after blood loss?
Operates over a period of days to weeks
Immediately after acute loss, small preformed albumin are transferred into circulation
Bulk is restored by hepatic synthesis over 3-4 days. Red cell is stimulated by EPO from the kidney as a response to low O2 tension.
What are the effects of acute loss of blood volume? (less than 10%)
10% or less: MAP normally unchanged, but pulse pressure declines (nonhypotensive haemorrhage). This is because the neurally mediated reflex mechanisms are enough to maintain homeostasis
There is also no change in baroreceptor firing, but there is a significant decrease in firing of cardiac receptors, causing aldo and ADH to increase substantially, as well as HR and inotropy
What are the effects of acute loss of blood volume? (more than 10%)
Fall in systempic MAP, causing reduced baroreceptor firing, aldo and ADH increase, and HR and inotropy increase
Resistance and capacitance vessels constrict
Sometimes, organ beds may be shut down
In extreme and uncompensated loss for long periods, haemorrhagic shock occurs and replacement may not be able to restore health.
How does the cardiovascular system deal with postural changes
Most cardiac filling occurs while lying down. Then standing, the blood has higher hydrostatic in the lower extremities, so Stroke volume drops as the blood moves into the ISF due to increased pressure
What is the difference between baroreceptors and cardiac receptors?
Baroreceptors buffer short term changes in pressure around a set point
Cardiac receptors are not involved in beat to beat regulation of pressure, and contribute to setting the set point that baroreceptors work around
How is potassium buffered in the body?
Transcellular gradients- fast, rapid equilibration
Renal excretion and tubular buffering, reabsorption in the DCT and CD- slow
Describe the effects of insulin in the body
Promotes: - Glucose uptake in muscle and adipose tissue - Glycolysis - Glycogen synthesis - Protein synthesis - Uptake of ions (potassium and phosphate) Reduces: - Ketogenesis - Proteolysis - Lipolysis - Glyconeolysis - Gluconeogenesis
What are the hormones that regulate glucose and lipid metabolism?
Insulin
Counterregulatory- glucagon, adrenalline and catecholamines, HGH, cortisol
How do insulin levels change over a day?
At night, our insulin levels are very low. Steroid levels are highest just before we wake, and lowest in the middle of the night
We still increase our blood sugar after eating, and reduce it afterwards- we can’t trigger insulin before the glucose is absorbed (though this practice works well in treatment)
Insulin concentration gradient is greatest after a meal.
How does insulin work?
It binds to its receptor and stimulates the GLUT4 transporter to move glucose into the cell
How are ketones formed?
We transform triglycerides from fat into non-esterified fatty acids and glycerol (done with lipase, but inhibited by insulin).
We then stimulate B-oxidation (done by glucagon) to form ketones using Acetyl CoA via the krebs cycle.
What is required to form ketones?
Lack of insulin
Excess glucagon
What are the main ketones and what does the presence of different types suggest?
Acetoacetate
Beta Hydroxybutyrate
Acetone
Acetoacetate and B are in an equilibrium- B is stimulated when there is more free H+ present, so is often there in acidosis.
How do the ketones fare in acidotic conditions?
In acidoses, there is more H+ in the circulation, forming CO2 and H2O and lessening HCO3-. The ketone bodies then circulate as anions, increasing the anion gap.
In DKA, bicarbonate is replaced by B and acetoacetic acid, with the decrease in HCO3- approximating the increase in anion gap
How do the ketones affect DKA treatment?
If the acidosis is reduced, and the H+ is converted to CO2 and H2O, we have NaB and Cl- left over. Ketones are excreted as their salt. Cl- shows none of this loss
We normally replace volume loss with 0.9% NaCl to salt load, but end up with hyperchloraemia after treating DKA- fixable by the kidneys
(Note that treatment with insulin reduces B)
Describe urine ketones and what they can indicate
Measured using acetoacetate, as B cannot be detected, and the two are normally equal
(note that in acidosis B increases to 3-5:1, meaning that urine ketones underestimate the severity of ketonaemia
What are the criteria for DKA?
Hyperglycaemia
Acidosis below 7.3/bicarbonate <15
Presence of ketonaemia or ketouria
(proposed change replaces last point with “serum B level of more than 3)
What causes DKA?
Lack of insulin plus physical stressor (illness, UTI etc) due to overstimulation of counterregulatory hormones that promote ketone formation
How does potassium sit in the body>
98% is intracellular
How does the body process an influx of potassium?
In potassium intake, extra potassium is shifted into cells, and then slowly removed and excreted
This means we have feedforward control, which is rapid and anticipatory.
This allows K to begin to be excreted before we see an increase in plasma ECF (the sensors are located in the gut)
How does insulin affect potassium handling?
Insulin causes upregulation of Na/K ATPase, resulting in increased K uptake (can be used to treat hyperkalaemia!)
Consumption of a glucose rich meal therefore stimulates K shift independently of K content. Some evidence for glucagon and cAMP, meaning a protein rich meal increases these, causing glucagon release into the portal vein, increasing the transtubular potassium gradient, GFR and doubling potassium excretion
How is potassium controlled by negative feedback?
This is a backup for any major changes. It is mainly done using aldosterone, which increases uptake by cells throughout the body, as well as stimulating renal excretion
Aside from insulin and aldosterone, what other factors influence potassium?
B2 adrenergic stimulation with epi and norepi. This causes K shift from ECF to ICF.
Continuous contraction and relaxation of muscles causes extrusion of K from the cells, and these shift the K to be taken back up afterwards
Acidosis increases K loss from cells, likely by inhibition of Na/K ATPase exchanger
Cell lysis causes ICF K to be released into the ECF
Increased ECF osmolarity causes water to be pulled rom cells, increasing relative ICF K conc, causing it to diffuse down its conc gradient into the ECF (and vice versa).
This extra potassium tends to be excreted by the kidneys, thanks to aldosterone, causing a net whole body loss of potassium
Describe how potassium is processed in the kidneys
It is reabsorbed early on in the nephron, and secreted later on
Reabsorption happens mostly in the PCT, some in ascending thick LoH by N/L/2Cl channel.
Secretion occurs through the DCT and collecting duct- where most of the variation occurs.
About 4% remains by the time the DCT is reached, though due to excretion the body can secrete more than initially filtered out by the GFR
The kidney is slow to conserve K+
K+ depletion and hypokalaemia can result if K+ intake is restricted
What factors determine K+ secretion?
- Activity of Na/K ATPase on basolateral membranes of intercalated cells
- Permeability of the luminal membrane
- Electrochemical gradient from lumen to blood
(Aldosterone works on the principal cells of the CD and causes changes here slowly)
What causes distal potassium secretion?
Increased serum K+
- Over 4.1, there is a steep nonlinear effect on K+ secretion
Distal tubular flow rate
- Increased distal flow increases secretion, as if you have a higher flow rate, there is less reabsorption time, and an increased gradient between the lumen and the blood
Decreased flow increases serum potassium as in severe renal impairment
(Diuretics increase flow and decrease serum potassium- similar to diabetes effects)
Aldosterone
What does acidosis or alkalosis mean for potassium secretion?
Acidosis decreases K+ secretion due to effects on Na/K ATPase
Alkalosis increases secretion
What are the lipids?
Plasma lipids include cholesterol, found in membranes, bile salts and as steroid precursors, as well as triglycerides, fatty acids and phospholipids
What are the different types of cholesterol?
LDL- adverse effects. Transport from liver to peripheral tissues. Predisposes atherosclerosis
HDL- beneficial effects- delivery from periphery to liver. Good prognostic sign. Slows atherosclerosis
Triglycerides- adverse vascular effects and pancreatitis
Why do we lower cholesterol?
Primary prevention: Reduction in vascular events, but small effect on mortality
Secondary prevention: Large beneficial effects, reduced CVS mortality and morbidity
(Total cholesterol 1mmol/L reduction causes a 25% decrease in vascular effects)
Different risk factors also synergize, so all need to be targeted
How do you assess high cholesterol?
History- look for signs of end organ damage
Exam- check BP, xanthoma, xanthelasmata
Investigations- urea, electrolytes, fasting cholesterol, LDL, HDL, Trigs
Glucose and ECG
Who do we treat for high cholesterol?
In secondary prevention in those post angina, MI, CVA, PVD, or diabetics
Also in primary prevention for those with CVS risk >30%/10 years
What are some treatments for high cholesterol?
Lifestyle changes
Drugs
- Statins (lower total, LDL chol, trigs. Increase HDL). Eg. simvastatin
- Fibrates (lower trigs lots, increase HDL) eg. bezabifrate
- Exetimibe (decrease TC and LDL)
- Nicotinic acid (lower trigs only)
Describe statins
Used in high CVS risk patients, diabetics, and for familial hypercholesterolaemia
Also used in secondary prevention after MI, angina, VCA, PVD, TIA.
They competitively inhibit HMG CoA reductase, causing reduced cholesterol synthesis, as well as stimulating hepatocytes to increase LDL receptors on their surface, stimulating uptake of circulating LDL
Metabolized by CYP3A4, so can interact with drugs
What are the side effects of statins?
Myalgia
Myositis (stop if creatinine kinase increases markedly)
Rhabdomyolysis
Deranged LFTs (Stop when ALT at 3x)
Fibrate, amiodarone, verapamil, diltiazem, erythromycin interaction
Teratogenic
Rarely causes diabetes
Describe myopathy with statins
Occurs in 1/10000 per years
Related to statin concentration
What other beneficial effects do statins have?
They are also anti-thrombotic and anti-inflammatory
They modulate the immune system, and have some benefits occurring even before cholesterol decreases
Describe fibrates and how they work
Eg Bezafibrate
Indicated for isolated hypertriglyceridaemia (as well as diet, exercise, weigh loss, alcohol and diabetes interventions)
Also for combined therapy with statins for resistant hypercholesterolaemia
It is a PPARa agonist, which causes reduced VLDL production, and increased clearance as well as increased skeletal muscle fatty acid storage.
It also causes lipoprotein lipase to break down triglycerides
What are the side effects of fibrates?
GI upset
Deranged LFTs
Myositis (risk increases with concurrent statins)
Describe Ezetimibe
Low efficacy as monotherapy, but used with statins
It reduces cholesterol absorption, delivery of cholesterol to the liver, increases LDL receptor expression in the liver, and affects enterohepatic circulation
It blocks a channel bringing cholesterol in from the gut
What are the side effects of ezetimibe?
Abdominal pain
Diarrhoea
Describe nicotinic acid
Also known as vitamin B3
very rarely used unless in combination therapy
Causes reduced fatty acid mobilisation from the periphery, reduced TG/VLDL production, and reduced HDL degradation
What are the side effects of nicotinic acid?
GI intolerance
Flushing
Dry skin
Describe sequestrants (bile acid binding resins)
Now uncommonly used
Drugs such as cholestyramine bind bile acids, stopping enterohepatic circulation, reducing exogenous cholesterol absorption, increasing conversion of endogenous cholesterol to bile acids, and increasing hepatic LDL receptor expression
What are the side effects of sequestrants?
Many GI side effects
Impairment of ADEK absorption and absorption of other drugs like digoxin, warfarin, thiazides etc
Describe effective lipid lowering treatment
Often lifelong, with side effects
There is lots of evidence of CV benefit
However, detection and active treatment needs to be improved
What are some new directions in cholesterol treatment?
PCSK 9 inhibitors- decrease LDL by prolonging the life of the LDL receptor
Also monoclonal antibodies (evolocumab) and an RNA inhibitor (inclisiran)
How does acidity change as blood travels through the body?
as it moves through the capillaries, it collects co2, causing it to become more acidic the more capillaries it has passed. This is done by pushing equilibrium towards bicarbonate
How does the respiratory system regulate pH?
pH = 6.2 + log10[HCO3-]/[0.03xPCO2]
PCO2 is proportional to VCO2/VA.
How do changes in pH get detected and affect the respiratory system functions?
Arterial PCO2 and pH are sensed by chemoreceptors in the brain and aortic/carotid bodies
Centrally, increased pCO2 and pH stimulate ventilatory drive and vice versa, via the ventrolateral medulla
Hypoxia is sensed peripherally and also stimulated ventilatory drive
As hydrogen ions don’t cross the BBB, central chemoreceptors actually sense CO2 and other secondary changes in pH due to metabolism/resp changes
Increased CO2 is the main driver of respiration
Describe the relationship between ventilation, PO2 and PCO2
PO2 is a nonlinear stimulus of ventilation, with a great increase in drive only occurring at PaO2 at 60 or lower- not potent
PCO2 is linear and potent
How do we maintain and control our levels of bicarbonate?
Requires:
- Reabsorption of all HCO3-
- Regeneration of all HCO3- lost in the buffering of nonvolatile acids
- Removal of fixed acids incorporated into the non-bicarbonate buffer systems
Done in the PCT
How is HCO3- lost in the urine?
The Na/KATPase causes exchange of 3 sodium into the blood for 2K+ into the cell/. There is therefore a built in gradient of sodium- high outside the cell, low inside. This causes a negative cell potential.
The Na/H Antiporter causes H+ to be secreted into the lumen of the tubule in exchange for Na+. The H+ joins with the HCO3- to cause H2CO3.
Carbonic anhydrase on the luminal surface of the cells cases it to form CO2 and H2O, which are then freely diffused into the cell
This then reacts again to form H+ and HCO3-. The bicarbonates then move down the electrical gradient to outside the cell.
However, this also causes some sodium to be moved with it
How is bicarbonate produced in the kidneys?
Glutamine is converted by a dehydrogenase into glutarate. This is then released as glucose and bicarbonate. It also produces ammonium, which is exchanged for sodium to move the NH3 into the tubular lumen, where it joins with H+ to form NH4+. Cl- also joins on to this, allowing the whole molecule to be excreted
How do hydrogen ions’ excretion result in acid excretion?
It joins with NH3 as well as HPO42- to excrete these acids
How does acidosis/alkalosis affect renal function?
Secretion of H+ by the nephron is increased, and nearly all HCO3- is reabsorbed.
Alkalosis: vice versa
HCO3- is inversely related to plasma Cl- as they share the same electrical gradient. A loss of Cl- means bicarb has to be reabsorbed, causing alkalosis
Describe the relationship between bicarbonate and aldosterone
HCO3- is inversely related to plasma K+. This is increased by corticosteroids like in cushing- high levels of aldo lead to high ECF HCO3-
This is because aldo cause Na sparing and K and H+ wasting via the Na/H antiporter. H loss is matched by increased HCO3- reabsorption, causing metabolic alkalosis with hypochloraemia and hypokalaemia, often with expanded ECF volume
What is the kidney’s response to respiratory alkalosis?
Decrease secretion of hydrogen ions
Reduce reabsorption of HCO3-
Reduce renal net acid excretion to restore pH, but reduces HCO3- reabsorption
What is the body’s response to metabolic acidosis?
Increase ventilation to induce slight hypocapnia
We know it’s chronic when a small amount of acid is being produced to try to compensate- resulting in a smaller than expected base excess
What is normal blood pH?
7.37-7.42
How is acid produced in the body?
Through oxidative metabolism, which produced CO2
Protein catabolism
How do we control acid levels in the body
Via buffering (transient, so short term) Excretion (regulates long-term) This is done either in the lungs (CO2 removed via gas exchange) or in the kidneys (acid from proteins catabolism)
What is the volatile acid and how is it regulated?
Carbonic acid
H2O + CO2 H2CO3 H+ + HCO3-
What are fixed acids and how are they regulated?
Those produced by protein catabolism, eg. H2SO4
Doesn’t equilibrate, and therefore is excreted in the kidneys
Increases in ischaema or extreme exercise (lactic acid) or DKA (B hydroxybutyric acid)
Describe the reaction of the body to CO2 changes
For a given pH, as CO2 increases, bicarbonate also increases. This is because the CO2 is beginning to be converted to HCO3- to buffer it out. As H+ increases, pH drops, and we get acid combining with bicarbonate, causing it to drop again
Describe the body’s response to nonvolatile acids
Bicarbonate is the main extracellular buffer, and so blood and ECF is good for short term buffering
H+ combines with intracellular proteins/organic phosphates in tissue and bone
They are transported across the cell membrane in exchange for Na+ and H+. This is a slow process
Ultimately, fixed acids are excreted by the kidney
Describe the assessment of pH from different sources
Bicarbonate, phosphate and protein buffer systems all use the
ka = [H+][HCO3-]/[H2CO3]
style system
However this is not good for calculating intracellular pH, as it isn’t homogenous with the ecf
Describe how volatile acids are buffered
If CO2 is added, the bicarbonate increases, and pH decreases due to acidity
In the plasma, it is buffered by non-bicarbonate buffers, such as phosphate and acid proteins
In The RBCs it is buffered to produce HCO3-, as well as being used to bind to amino groups attached to the Hb. It forms an equilibrium with carbamino Hb
This causes red cells to swell slightly, as well as causing the Hb to release O2
How is CO2 eliminated from the lungs?
Carbamino Hb is responsible for 30% of the CO2 eliminated from the lungs
As O2 falls, the Hb becomes reduced in capillaries, making it a better base and therefore a better buffer
What is the haldene effect?
An increased ability of the blood to carry CO2 when oxyHb is decreased. This is because DeoxyHb is more effective than oxy at forming carbamino compouds
Besides carbamino Hb, how else is CO2 carried in the blood?
Chloride shift accounts for 60% of CO2 carriage, as it enters the cell, causing a switch with bicarbonate exiting the cell. This attaches to CO2 in the plasma, carrying it out towards the lungs
10% dissolves
H+ is also buffered by histidine
What is base excess/base defecit?
Base excess appears in metabolic acidosis, and is measured by titiration of a blood sample with a strong acid to pH 7.4 at a standard PCO2 and temp
Base defecit is there reverse
What causes respiratory acidosis?
Inadequate ventilation to clear enough CO2
What causes respiratory alkalosis
Overventilation relative to degree of CO2- like anxiety, or overbreathing
Causes lightheaddness, limb tingling- need to place bag over nose and mouth
What causes metabolic acidosis?
Excess acid production due to ischaemia, DKA or reduced excretion by kidneys or loss of bicarbonate (due to tubulopathy in PCT, bicarbonate wasting, congenital issue, diarrhoea)
What causes metabolic alkalosis?
Vomiting, loss of acid production
What acid base disturbance does vomiting cause?
Metabolic alkalosis- loss of HCl from the stomach if severe and recurrent
What acid base disturbance does diarrhoea cause?
Mild acidosis, normal CO2 and low bicarbonate due to potassium and bicarbonate loss
What acid base disturbance does hyperventilation cause?
Respiratory alkalosis
What acid base disturbance does asthma cause?
Mild acidosis, high CO2 and a base excess
Describe how bicarbonate is regulated by the kidneys
If plasma bicarbonate is more than 24mmol/L it is excreted by the kidney. Anything under this promotes reabsorption and regeneration of all filtered HCO3-, and excretion of filtered fixed acid
What does metabolic alkalosis require, if HCO3- is maintained so carefully?
There needs to be both an initiator as well as an impaired renal correction mechanism
What can initiate metabolic alkalosis?
A gain of alkali in the ECF May be exogenous (IV infusion, citrate in transfused blood). May be endogenous (metabolism of ketoanions to produce bicarbonate)
May be a loss of H+ from the ECF. May be from kidneys (diuretics) or gut (vomiting of gastric fluid, NG suction, infant pyloric stenosis)
How does chloride affect bicarbonate reabsorption?
A lack of chloride increased HCO3- reabsorption. This because Cl- and HCO2- are the only anions present in appreciable concentrations in the ECF. Due to Na+ and K+ reabsorption we need to reabsorb some balancing anions to maintain electroneutrality- deficiency of one increases reabsorption of the other.
What causes risk of alkalosis in terms of Cl-?
If the person is volume depleted due to a diuretic, they will increase their aldosterone levels and losing NaCl, causing increased bicarb reabsorption. A low salt diet can also do this
Describe how potassium depletion affects acid base status
Rare but important
Can be due to hyperaldosteronism- either primary or secondary
Increased distal tubular sodium reabsorption increases K and H loss. Increased HCO3- reabsorption matches the increased loss of H+, so you shift electroneutrality further in favour of K and H loss
This can happen in 2 ways
Indirect: Increased Na reabsorption causes increased negative cell voltage promoting H+ secretion
Direct: Stimulation of H+ ATPase, upregulating the anion exchanger and facilitating HCO3-/Cl exchange
What is the anion gap and what does it tell us?
It is the difference between the concs of major cation (Na+) and anions (HCO3-, Cl-). iF the anion of the nonvolatile acid is not Cl- (eg. lactate or B hydroxybutyrate) the anion gap will increase, suggesting that acid is being produced in the body.
How can respiratory physiology help us to determine facets of acid base issues?
We can use the alveolar arterial gradient:
PAO2 = 150-PACO2/0.8 +2
Substract PaO2 from this. Over 25mmHg difference in elderly or 12 in young indicates impaired lung diffusion
How does COPD affect acid base status?
The compensation is metabolic alkalosis due to increased CO2 retention- HCO3- will elevate in response and pH will drop
Note that if there iw an ongoing metabolic acidosis the HCO3- may be normal, and pH may be slightly lower than expected.
How does oxygen affect acid base conditions?
If there is limited O2 delivery to the tissues, lactic acidosis may develop due to ischaemia
Can be determined with an anion gap
Describe conditions involving normal heart rhythm, bradicardias and tachycardias
Normal- involves ectopics
Bradycardias- involves AV or SN conduction disorders
Tachycardias- includes automaticity and triggered activity issues as well as reentrant mechanisms
Where do arrhythmias come from in bradycardias vs tachycardias?
Bradycardias: Physiological from the sinus node, AV node, or neurally mediated
Tachycardias: Can be atrial, junctional (supraventricular tachycardia) or ventricular due to a scar
What are the different cardiac devices?
Single chamber: AAI/VVI Dual chamber (DDD) Pacemaker or ICD (Implantable cardiac defibrillator
What are the functions of implantable cardiac devices?
Helps with rate support, AV synchrony, VV synchrone, monitoring, syncope etc
Good for those at risk of sudden cardiac failure
What are the indications for different cardiac devices?
Pacemaker:
- Used in high grade AV block (second, third or complete)
- Symptomatic sinus node disease
ICD: Used for people who have had aborted sudden cardiac death
- Sustained VT in structural heart disease
CRT:
- Used for cardiomypoathy and Left bundle branch block
Describe ectopy
A common condition, but the majority are benign- Assessment can be examination and an ECG/echo
Treat either with reassurance, or with suppressive drugs such as B blockers and class 1 agents.
Can also withdraw responsible drugs, manage the underlying condition, or insert a device/perform a surgery.
Give an overview of vaughan williams class 1 drugs
Sodium channel agents (mostly blockers)
1A reduce Vmax and prolong APs by decreasing conduction velocity and prolonging refractoriness- eg. quinidine, procainamide
1B shorten AP without affecting Vmax by decreasing the refractory period- phenytoin, lidocaine
1C reduce Vmax and slow conduction but don’t affect the refractory period
What is VW class II?
Beta blockers, such as metoprolol, atenolol etc
Blocks the B adrenergic system, decreasing sympathetic tone
Can result in fatigue and bradycardia- so start low, go slow
Contraindicated for asthma but not COPD
Prescribed for atrial and ventricular arrhythmias
What is VW class III?
Potassium channel blockers to increase repolarisation
- Sotalol, amiodarone
Can affect defibrillation thresholds- amiodarone increases, sotalol decreases.
Reduce digoxin with amiodarone
Toxic levels may build up
What is VW class IV?
Slow calcium channel blockers
- Verapamil, diltiazem, nifedipine
How do antiarrhythmic drugs work?
They affect the cell membranes, ANS and vagal tone
Increased vagal tone decreases HR, slows AV node conduction and decreases SA node automaticity
Cell membrane activity affects the conduction velocity, length of the refractory period, and automaticity of the SA or AV node.
How do digoxin and adenosine affect arrhythmias?
Digoxin: Increases PNS activity to slow atrial rate and AV nodal conduction
Adenosine- typically IV bolus. Causes AV node block
How do we treat AV nodal reentrant tachycardia?
Can do medical therapy (adenosine when needed)
Or ablation therapy
Describe atrial fibrillation
Common with varying symptoms. Need to aim for either rhythm (sotalol) or rate (AV node slowing) control.
Issues with anticoagulation
Describe VT
Can be reentrant or an automatic trigger around or in scar tissue
VT invades the rest of the ventricles with a broad complex, activating the whole chamber through cell to cell contact rather than the fast conduction His Purkinje network
The atria contract and activate independently
Describe the management of VT/VF
VF- emergency resuscitation
Need to treat underlying pathology- ischaemia, bradycardia, structural, metabolic or drug causes
Give anti ischaemic and ACEi drugs, antiarrhythmics (Class II/III), potentially implant an ICD or pacemaker, and potentially surgery
Describe amiodarone
Side effect profile is large- myalgia, gait disturbance, insomnia, interaction with warfarin
Issues with loading doses
Toxicity can cause pulmonary fibrosis, hypo/hyperthyroidism, liver failure, bone marrow suppression, renal failure, photosensitivity, and corneal deposits
