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BMS 109 > CDL > Flashcards

CDL Flashcards

1
Q

What is pharmacogenomics?

A

Part of personalised medicine- The study of how a person’s genes influence their response to medication.
e.g. drug metabolising enzyme polymorphisms.
Can reduce trial and error prescribing, and avoid adverse reactions.

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2
Q

Personalisation problem with diabetes patients?

A

43% of diabetes patients say drugs don’t work and 5% have hospitalised adverse reactions.

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3
Q

What revolutionised personalised medicine?

A

In Genome project in 2003- before only 4 drugs that use pharmacogenomics, but 10 years later around 104.

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4
Q

WHAt is pharmacogenomics.

A

the branch of genetics concerned with determining the likely response of an individual to therapeutic drugs.

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5
Q

What medicines are personalised medicines important for? (4)

A

Warfarin, familial hypercholesterolaemia (FH), heart transplantations0 allomap test for aorund 20genes which predict rejection, PLavix/clopidogrel.

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6
Q

Plavix other name? For?

A

Clopidogrel, antithrombotic drug for patients with heart disease, stroke or heart attack (combined with aspirin)

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7
Q

Why is clopidogrel personalised?

A 
The enzyme (Cyp2C19) which metabolises clopidogrel into its active form can have polymorphisms so some people may have reduced enzyme activity. Therefore, these people will need a higher dose as less is converted into the active form. 
Also learnt about any drug interreactions e.g. if take with Omeprazole which Inhibits Cyp2C19 can have 40% less active metabolite made, making the Clopidogrel less effective.
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8
Q

What is pharmacokinetics?

A

Movement of drugs around the body e.g. stored in fat etc if have high fat content. Think about anaesthetic levels.

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9
Q

What is pharmacodynamic variation?

A

Individualised response e.g. measure the patients platelet function, BP etc and adjust drugs warfarin, anticoagulants etc accordingly- do at the bedside. Monitor dose dependent upon patient response. Balancing act.

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10
Q

Which graphs are best to show clinical trial results before and after a drug?

A

Inter-variation graphs- so show the before and after plotted point for each individual patient and a line to link them with the slope of the line representing the percentage change- this shows individual responses e.g. may look like no difference before and after drug if all plotted as a mean on bar chart, but actually half ppatients have big increase but half decrease- could need further study maybe genetic reasoning for example.

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11
Q

Factors that cause inter-individual variation? (6)

A

Age, ethnicity (superseeded by genomics largely now and diet) genetics, immunologogical factors, concomitant diseases, drug interactions.

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12
Q

Age impact on inter-individual variation response to drugs?

A

GFR- e.g. newborns 20% lower than adults, less drug elimination- eg. Digoxin, half life adult 40hours, neonate 200h, elderly 80hrs.
Drug metabolising enzymes may have fewer/less active in newborns, and elderly body composition changes with age and interact with other drugs etc

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13
Q

Ethnicity impact on inter-individual variation response to drugs? Examples (2)

A

e.g. Hydralazine (for heart failure reduces BP, so reduces afterload ,so increases CO).
In African/American v effective when using nitrates with- reduces pre-load. Whereas white other drugs better.
or Chinese- ethanol dehydrogenase enzyme deficiency in higher percentage.

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14
Q

Genetics impact on inter-individual variation response to drugs?

A

polymorphisms (snps): alternative sequence at loci on allele.
e.g. SNP in factor V Leiden in a coagulation factor gives inherited thrombophilia- clots.
E.g. Many inherited mutations cause diseases.
e.g. changes in machinery like fast/slow acetylators, which affects the clearance of drugs- like hepatic acetyl transferase.

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15
Q

Concomitant diseases?

A

Diseases affecting the kidney or liver- they affect clearance of a drug, or metabolising or detoxifying etc. Can Prolong and intesify effects.

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16
Q

Concomitant disease impact on inter-individual variation response to drugs?

A

Diseases that influence receptors e.g. Familial Hypercholesterolemia- statins don’t work as they have faulty LDLR on liver (needed for LDL-cholesterol removal from blood) so PCSK9 inhibitors have benefit.

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17
Q

Drug interactions impact on inter-individual variation response to drugs?

A

When drugs interact with each other- pharmacodynamic interactions

e. g. Sildenafil mechanisms of action potentiates nitrates which can lead to hypertension.
e. g. Diuretics- used in heart failure, lowers plasma K but predisposes to digoxin.

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18
Q

Example warfarin genes that affect dose?

A

CYP2C9-enzyme that metabolises warfarin- normal (one star) or slow (two or three stars)
VKORC polymorphisms in promoter- this is the warfarin target.

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19
Q

What is end point analysis?

A

A marker at the end point e.g. Statins, cholesterol levels not CVD, or blood pressure not MI etc- no guarentee relationship.

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20
Q

What happens when the heart muscle contracts?

A

The muscle contracts, reducing he volume of the myocardium, ejecting blood out

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21
Q

Average how many beats per min of heart?

A

70hb/min

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22
Q

The heart is..

A

its own pacemaker- controls its own contraction rhythm and rate

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23
Q

5 phases of the cardiac AP?

A 
0-Rapid depolarisation 
1-Partial repolarisation
2-plateau
3-repolarisation
4-pacemaker potential
(in nodal cells)
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24
Q

Phase 4 of the cardiac AP?

A

Pacemaker potential:
Gradual inward Na (or Ca) leak, and decrease in outward K leak. Depolarises the myocardiocytes to -60mv which is the critical threashold to open Na channels.

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25
Q

Resting potential of the cardiac AP?

A

3Na out 2K in through Na/kATPase. -70mv (never statically at due to pacemaker potential)

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26
Q

Phase 0 of the cardiac AP?

A

Rapid Depolarisation:
After threshold is reached (from pacemaker potential), the rapid repolarisation from -60mv to 40mv is achieved by opening the Na channels (resting 3Na out 2K in) na rushes in (+). High K inside cell, but high Na and CA outside.

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27
Q

Phase 1 of the cardiac AP?

A

Partial Repolarisation:

Na influx is stopped but K still leaks out- so from 40mv to 0mv.

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28
Q

Phase 2 of the cardiac AP?

A

Plateau:
(0mv to -20mv) K leak stopped, but slow inward Ca current maintains the depolarisation of the myocardiocytes.
This is the refractory period to slow the cardiac AP in nodal cells, else they can fire 100 times a second which would be way too fast for the heart to fill up and eject blood, causing tetany (sustained scontraction) where cant pump blood.

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29
Q

What could cause tetany of the heart?

A

(sustained scontraction) where cant pump blood. Lack of slow inward Ca current, would stop the plateau phase, which causes the heart refractory period to stop firing again too fast.

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30
Q

Phase 3 of the cardiac AP?

A

Repolarisation:
(-20mv to -70mv) Inactivation of the slow inward Ca channel. Increase in outward K leak current, resets neagtive potential. So high K inside, high Ca and Na outside (Na/K ATPase returns)

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31
Q

When is the Ca channel open/closed in the cardiac AP?

A

Closed during depolarisation.
Opens in the plateau phase- inward Ca current (make inside more +).
Closes during repolarisation.
Pacemaker potential gradual leak of Ca or Na in.

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32
Q

When is the Na channel open/closed in the cardiac AP?

A

Na inward channel is opened at threshold (after gradual depolarisation to -60mv). Shortly after repolarisation the Na channels snap shut. Na is returned outside by the Na/K ATPase.

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33
Q

When is the K channel open/closed in the cardiac AP?

A

K outward leak, the leak stopped during the pacemaker potential stage (so depolarises inside +). After depolarisation the K starts to increase (after plateau) helping to repolarise the myocardiocyte.

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34
Q

Path of the wave of depolarisation across heart muscles?

A

SAN initiates from nodal cardiac potential, the wave of excitation travels to R atria to fire off APs (contraction).
Impulses get to the AV node (delay of conduction through)- down the budle of Hiss. Rapid conduction down Purkinje fibres of ventricles causing contraction here.

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35
Q

Role of the AV node?

A

Delays AP through- allows the atria time to contract before the ventricles contract, so allow the blood to be pumped nto the ventricles before they contract and eject blood out of the heart. ALso can take over to initiate an AP if needed (also purkinje)

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36
Q

What is ectopic rhythm?

A

If the SAN node fails the AV node can take over to initiate contraction of the ventricles and can keep you alive.

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37
Q

Difference in cell APs in nodal cells vs myocardiocytes?

A

Calcium is rapidly influxed at depolarisation instead of Na. With K maintaining it.

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38
Q

Two types of arrhythmia and two examples of each of those?

A 
Abnormal impulse generation: 
-Triggered activity
- Increased Automaticity
Abnormal impulse propergation
-Heart block
-Re-entry
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39
Q

Triggered activity is what? Caused by?

A

(Delayed after depolarisation)
If stimulate the heart muscle in short sucession, Too much Ca intracellularly accumulates- depolarises the myocardiocytes mv above critical threshold value- initiates another AP. Fire ectopic beats.

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40
Q

Increased automaticity impact?why?

A

ectopic beats due to the SA node spotaneous activity increasing, contraction in other places in the heart as ectopic beats driven to other places in heart, increasing HR

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41
Q

Re-entry impact why?

A

No electric passage through certain heart tissue (heart block) , can cause circus movements (re-entry)- Refractory tissue left behind wave of excitation which cannot be repolarised, so travels in only one direction. Normally in a circle will reach the top and split and join back at the bottom, but if one way blocked can only go one direction an then can keep going round the circle (if unidirectional block) and by the time it gets to the top its ready to fire again, so keeps going round the circle

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42
Q

First degree heart block?

A

Atrioventricular block.

Delayed P to V depolarisation (delay at AVN normalyl 100ms) all beats happen just slower

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43
Q

Second degree heart block?

A

Can get dropped beats= get P waves but no V after. Can result in faiting, dizzyness. AV delay above 200ms

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44
Q

Third degree heart block?

A

Atria and ventricular contraction completely independent of each other, ventricles take over as pacemaker and contract themselves. Cycle slower. Fainting, fatigue, palpitations etc, can cause death.

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45
Q

Sinus bradycardia? Tachycardia?

A

Sinus= normal rhythm from SAN
Normal bradycardia- when sleep HR decreases.
Normal Tachycardia- when exercise HR increases

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46
Q

Atrial tachycardia?

A

tachycardia of the atria- contract rapidly but due to the delay through the AVN not all get through to the ventricles (protective)/

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47
Q

Ventricular tachycardia?

A

Multiple waves in ventricles, very serious

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48
Q

Atrial fibrillation?

A

Atria dont contract just fibrillate- disorganised often fast. No output from atria-the excitation some just circles back to the SAN. 1/20 over 65yr olds have.
Inefficient irregular heart rhythm, blood can pool in the atria causing a thrombus- stroke.
No true P waves, but ventricles contract.

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49
Q

Drugs for atrial fibrillation?

A

Anti-coagulants- stop pooled atrial blood clotting and blocking an artery- stroke

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50
Q

Ventricle fibrillation?

A

No cardiac output-die.

Defibrillation can save

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51
Q

Autonomic sympathetic control on the heart?

A

HR increases.
E.g. exercise, fright, B1 adrenoceptors (CAMP stimulation). Increases the slope of the pacemaker potential so reaches threshol faster.
Increased automaticity

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52
Q

What is automaticity?

A

The fact that the SA has spontaneous activity. If increased- SA firing increases so HR increases etc

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53
Q

Autonomic parasympathetic control on the heart?

A

Heart rate decreases.
E.g. Vagal tone- keeps HR down- if take heart out body it will beat faster.
Decreases slope of pacemaker potentials.
to M2 muscarinic Ach receptors
decreased automaticity.
Vagus also inhibits atrialventricular conduction so increases the PR interval

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54
Q

4 classes of antiarrhythmic drugs?

A
  1. sodium channel blockers
  2. Beta blockers
  3. Prolong AP refractory period
  4. calcium channel blockers
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55
Q

How do sodium channel blockers help with arrhythmia?

A

Use- dependent e.g. only targets the channels that are o inactivated (which is the stage after open, so doesnt target the closed channels).
E.g. a. disopyramide, Quinidine,
b. Lidocaine (local anasthetic), Mexilitene
c. Flecainide, propafenone

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56
Q

How do beta blockers help with arrhythmia?

A

B adrenoreceptor antagonists (which sympathetic Hr increases)

e. g. Propanolol, carvediolol, nadolol (non-selective)
e. g. bisoprolol, metoprolol (B1 selective)

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57
Q

How do AP prolongers help with arrhythmia?

A

slow HR- prolong refractory period

e.g. Amiodarone, Sotalol-

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58
Q

How do Ca channel blockers help with arrhythmia?

A

Ca channel blockers stop some of depolarisation stop too much.
e.g. verapamil, diltiazem

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59
Q

What does Digoxin do?

A

Cardiac glycoside- inhibits the Na/K pump, which Maintains the resting potential and swaps ions back after AP so can fire again.
These encourage vagal tone to increase- slowing of AV conduction, bradycardia, increased intracellular Ca causes an increased force of contraction (inotropic), but can also cause ectopic activity

60
Q

Digoxin as a drug?

A

Narrow therapeutic range
Nausea, vomiting, diarrhoea, confusion

Used in atrial fibrillation (AF) to reduce ventricular rate response
Use in severe heart failure as positively inotropic

61
Q

QT prolongation can cause?

A

Can cause arrhythmia but also use to treat arrhythmias such as polymorphic ventricular tachycardia, ventricular fibrillation
e.g. Amiodarone and Sotalol

62
Q

Amiodarone drug? Use?

A

QT prolongation for ventricular tachycardia.
Widespread distribution of drug- takes a long time to get into system and stays for around 3 months after stop taking, but multiple drug interactions eg. displaces Warfarin etc.

63
Q

Amiodarone adverse effects

A

QT prolongation
Polymorphic ventricular tachycardia

Interstitial pneumonitis
Abnormal liver function (metabolised here)
Hyperthyroidism / Hypothyroidism- contains iodine.
Sun sensitivity
Slate grey skin discolouration if on 15+ years.
Corneal microdeposits disturb light into eyes.
Optic neuropathy

Multiple drug interactions e.g. Warfarin.
Very large volume of distribution and stays in body around 3 months after stop taking

64
Q

Ejection fraction?

A

60% at rest- %volume of blood that is ejected with each cardiac contraction at rest.
Measure of intrinsic contractility of heart.

65
Q

Stroke volume?

A

70ml, the volume of blood ejected in one heart contraction

66
Q

Cardiac output =

A

Stroke volume x HR

70ml x 70bp/min = 4.9l per min.

67
Q

Maximal cardiac output?

A

x7 to 35ml/min

As exercise both stroke volume and HR increase.

68
Q

Control of cardiac output brief?

A

HR: autonomic- sympathetic increases HR, para decreases. CHRONOTROPIC.
Stroke Volume: Intrinsic contractility (we cant change) or proload/afterload. INOTROPIC.

69
Q

drugs to increase heart rate?

A

Noradrenaline and ciculating catecholamines

70
Q

WHy may some people not have autonomic nervous control of their heart rate?

A

In the case of a heart transplant.

71
Q

How can intrisic Stroke volume be changed?

A

Intracellular contractility adjusted by Ca handling, availability of O2, FA, ATP etc.
e.g. Isoprenaline alters Ca.

72
Q

How can extrinsic stroke volume be changed?

A

Preload: (filling pressure)- volume and pressure of blood going into the ventricles before they contract.
Afterload: (Resistance to ejection)- after contraction the blood needs ejecting into circulation, and this requires different pressures depending on if vessels constricted(or hypertension)or relaxed

73
Q

Where is Ca stored? What stimulates release?

A

sarcoplasmic reticulum. The more Ca released the more is released. Ca induced Ca release. Ca binds to ryanodine receptors causing a second wave of Ca release into the myocardiocytes.

74
Q

What happens in the myocardiocytes when Ca is released?

A

Ca released- causes Ca release from SR (ryanodine-second Ca wave). Ca accumulates and binds to troponin, troponin moves tropomyosin out of the way so that myosin heads can bind to the actin filaments. Stretches the muscle, ATP is needed to release the cross bridge so the myosin can attatch futher up pulling the filaments even closer together and contracting the muscle.

75
Q

Quality of cardiac muscle which helps its role?

A

It is branched, which helps to conduct AP quickly and synchonised down the muscle.

76
Q

If have heart failure, for the same stroke volume the ..pressure needs to be higher

A

The filling pressure (preload), as the afterload is increased (e.g. hypertension, vasoconstriction etc.

77
Q

What is diastole?

A

filling stage- relaxed (die youre relaxed)

78
Q

What is systole?

A

contraction and ejection stage.

79
Q

Wat is Isoprenaline?

A

a synthetic catecholamine (like adrenaline) which increases sympathetic drive- so increases Ca in the muscles if measure, and increase contraction.
(in isolated muscle strip with no preload or afterload- so increases the intrinsic contractility of cardiac muscle)

80
Q

What is LVEDP?

A

Left Ventricular end diastolic pressure- pressure exerted with ventricles all full with blood not contracted yet- PRELOAD.

81
Q

For the same SV/ CO how can the SV vs LVEDP graph be shifted up or down?

A

FRANK STARLINGS LAW:
Up: Increased SV or CO for same preload: If decrease the afterload vasodilators etc. or increase contracility (e.g. isoprenaline, NorA)
Down: Decreased SV or CO for same preload: If got HF- damaged heart after MI contractility down or increased afterload e.g. vasoconstriction, hypertension.

82
Q

Heart failure frank starling graph? WHats happening?

A

Say heart scarred after MI, to maintain CO/ SV normally the heart would increase preload, but the graph line plateaus so doesnt increase CO much.

83
Q

Heart failure frank starling graph? Fix?

A
  1. LVEDP can be decreased using duiretics. If lower volume of blood, lower preload. Therefore instead of the patient having a high EDP if they move further backwards along that line they are back within normal range with little change in CO and still above ‘low CO point’. SO symptoms are not present for either and heart under less strain.
  2. Vasodilators- E.g. ACE inhibitors, decrease afterload. Shift the graph line upwards (higher SV per LVEDP) or Digoxin- incease contraction CO increases.
84
Q

How does digoxin increase contraction? Use?

A

inhibits the Na/K channel (Na out), which drives the Na/Ca pump (Na in, Ca out). So if Na/K inhibited, less driving force for Ca out, it accumulates. Ca induced Ca release from ryanodine receptors on SR, more Ca released- higher force of contraction of heart muscle.
Used in critical conditions as this also increases O2 requirement ATP etc, so vasodilators used long term.

85
Q

What is the issue with coronary arteries for supplying the heart?

A

Most organs blood supply comes from the inside, however the heart is supplied outside in, which is fine during diastole, but every time the heart contracts it cuts off its own blood supply.

86
Q

Coronary Blood flow=

A

Coronary blood flow (E.g. I)= Perfusion pressure( e.g. V) / resistance (R).

V- ie Pd pressure between top and bottom of coronary artery. Atrial Diastolic pressure and LVDP
R- Length of tube x Blood viscosity x diameter of tube (radius to the power of 4- (doubble radius x16 less resistance) contraction, relaxation largely controls coronary blood flow)

87
Q

Perfusion pressure worked out by?

A

Arteriole(aorta) diastolic pressure -LVDP- so pressure in the aorta vs preload. So the pressure pushing the blood out of aorta into coronary arties -the resistance of the L ventricles at the other end of the tube to the blood flow.

88
Q

myocardial oxygen consumption arresting, resting vs heavy exercise?

A

arresting (no beating only basal function): 2ml/min/100g
Resting: 8
Heavy exercise: 70

89
Q

Issue with the changing O2 demand of the heart during exercise?

A

x8 higher blood demand when exercise, but if fixed blood flow to heart problem, and heart is one of the worst perfused organs- only gets 5% with v little excess.

90
Q

Cardiac oxygen delivery=

A

arterial O2 concentration x Coronary blood flow

unless anaemic low haemoglobin )2 conc is usally maximal so depends mainly on coronary blood flow

91
Q

What is the aortic pressure? Pattern of trace?

A

The pressure in the aorta- At its peak as blood is ejected from the heart (systolic BP=120) gradually decreases until small increase as the aortic valves snap shut to prevent backflow into the heart as the heart relaxes, and gradually as the blood is pumped away reduces to the minum which is aortic diastolic pressure=80. (this is higher than LVEDP)

92
Q

WHat affects aortic pressure?

A

humeral factors e.g. NorA, endocrine), autonomic factors, local metabolities

93
Q

Where do the coronary arteries emerge from?

A

Aorta just above the aortic valve.

94
Q

Left ventricular pressure trace shape?

A

Passive filling stage increases a bit then stabilises, the increases as the ventricles contract to push blood out- to the peak at systolic BP (120). The ventricle then is empty and relaxes back down to LVEDP (around 0)

95
Q

Why is the aortic end pressure so much higher than the LVEDP?

A

(80 vs 0) Because the aortic pressure is supported by the closing valve-which prevents backflow and losing all of the hearts ejection pressure.

96
Q

What happens to the coronary blood perfusion if there is a tachycardia?

A

This reduces the time window for coronay flow, as the ventricular pressure rises earlier, so less filling in diastole, and also less time in diastole (this is the perfusion time before the heart contracts and cuts off its blood supply)

97
Q

What happens to the coronary blood perfusion if there is a raised LVEDP?

A

It is reduced.

98
Q

If coronary perfusion pressure drops what happens?

A

E.g. patient blood loss- fall in BP. Initially the heart will be under perfused.
AUTOREGULATION:
Decrease resistance (afterload) of vessels using vasodilators- increases the perfusion pressure again despite drop in aortic pressure.

99
Q

What causes vasodilation in autoregulation of perfusion pressure?

A

Local control by metabolites: e.g. Low O2, CO2 build up, K iones, H+ ions, lactic acid build up, Possibly via adenosine.

Neural/humeral control (less important)
e.g. alpha adeno (big vessels) or smal B2 adrenoceptors.

100
Q

WHat is stenosis?

A

Blockage in an artery

101
Q

Heart is an …. organ

A

Endocrine
As it secretes hormones as atria and ventricles stretch - e.g. Atrial natriuretic peptide (ANP) in atria. and BNP Brain natriuretic peptide- ventricles

102
Q

Effects of ANP and BNP?

A

High Atria/ ventricular pressure

  1. increase renal excretion of sodium- water follows- water loss. BP decrease.
  2. Relax vascular smooth muscle but dont vasodilate efferent in glomerulus- so keep pressure gradient.
  3. Increase vascular permeability.
  4. inhibit release of aldosterone, angiotensin II, endothelin, ADH- so water into blood doesnt incease.

Basically counterracts the renin-angiotensin system, decrease EXC Vol, decrease BP

103
Q

Cardiac naturic peptides pharmacology?

A

Metabolised by Neural endopeptidase. (NEP or neprilysin)
Can inhibit NEP to increase naturc peptides.
Novel drug for heart failure, e.g. Sacubitril is a neprilysin inhibitor, or simulate peptides with Valsartan –angiotensin II blocker

104
Q

NICE definition (roughly) of heart failure?

A

A complex clinical syndome of symptoms and signs that sugges the efficiency of the heart as a pump is impaired.

105
Q

Other definition of heart failure?

A

Abnormality of cardiac structure/ function leading to the hearts failure to deliver oxygen at a rate that meets requirements of metabolising tissue.

106
Q

Epidemiology of heart failure?

A

1million cases in the UK (2% pop) and 50% increase predicted in next 25 years (ageing pop- increases exponentially with age)
Around 50% higher in men than women.

107
Q

Ageing population statistics?

A

by 2032 16million of Uk pop over 65 (23%). and 3million over 85

108
Q

Hospital figures for heart failure?

A

5% of emergancy admissions are with 70% of hospitalisation, average 2week stay. 2% of NHS budget.

109
Q

Prognosis figures for heart failure?

A

30% mortaility in the first year and 10% every year after.

110
Q

Two broad categories of heart failure? (not acute or chronic)

A

Systolic dysfunction: Due to LV systolic dysfunction (doesnt always cause HF)
Diastolic dysfunction: HFPEF common in elderly (hypertension)

(or acute and chronic)

111
Q

Two cycles of blood flow from heart?

A

Pulmonary and systemic

112
Q

What is HFPEF?

A

Heart failure with preserved ejection fraction

113
Q

Most common cause of chonic heart failure? Treatment (vague)

A

Coronary artery disease- e.g. cholesterol blocks arteries (atherosclerosis) which causes ischaemia of the heart and so scar tissue forms where starved of oxygen.

So treatment mainly vasodilators via neurohumoral blockade (RAAS - SNS) and not from direct LV stimulants

114
Q

WHa symptoms are seen in LVSD but not other forms of heart failure?

A
  1. Reduced CO (forward flow) causing fatigue, exercise intolerance (fine at rest in grade 1 by 4 breathless at rest) and filling pressure increased but CO down.
  2. Increased filling pressure (backward pressure)
    - pulmonary oedema at night especially wake up breathless.
    - Increased pressure in venous system- fluid leaks out (hydrostatic higher) gravity to ankles etc, jugular vein conjestion
115
Q

High LVEDP means?

A

Pulmonary conjestion

116
Q

Low Stroke vol means?

A

Hypotension

117
Q

4 types of Diuretics? for HF?

A
  1. Thiazide and related- Weak so not for HF but hypertension
  2. Loop diuretics- fast acting used for HF e.g. Bumetanide, Furosemide,
  3. K-sparing diuretics- used for HF- SPIRONOLACTONE (increase oestrogen- breast sensitivity in males) affect R.A.S also + Amiloride (not HF)
  4. Aldosterone antagonists- weak but also affect R.A.S (renin- angiotensin system)
118
Q

Diuretics side effects?

A

Hypovolaemia (mainly loop diuretics)
Hypotension ( “ )

Low serum potassium (hypokalaemia)
Low serum sodium (hyponatraemia)
Low serum magnesium (hypomagnesaemia)
Low serum calcium (hypocalcaemia)

Erectile dysfunction 		(mainly thiazides)

Raised uric acid (hyperuricaemia – gout)
Impaired glucose tolerance- diabetes (mainly thiazides)
119
Q

Spirolactone stats on HF?

A

by 18months survival rate increased from 70 to 80%.

120
Q

Traditional combo treatment for HF?

A

Hydralazine and nitrates.
(H= arteriole dilator- reduces afterload so heart pumps into a lower resistance system.)
Nitrates- venous dilators- (veins can store blood so reduce LVEDP)-nitrates particularly benefit for afro caribbean

121
Q

Why are nitrates of particular benefit for afro-caribbean people?

A

GENETIC PERSONALISATION.

naturally have low renin levels so vasodilators help increase

122
Q

Trial on vasodilators on HF patients?

A

642men with HF symptoms- Prazosin (alpha blocker vasodilator) or hydralazine and isosorbide dinitrate or placebo.
Mortaility decreased 36% in 3 years and improved LVEF with hydralazine and nitrate.

123
Q

Explain the renin-angiotensin system?

A

Angiotensinogen is synthesised and released by the liver.
Renin (secreted from juxtaglomerular kidney cells) converts angiotensinogen into Angiotensin I.
ACE (angiotensin converting enzyme often in lungs or endothelial cels) converts angiotensin I into II.
Angiotensin II is a vasoconstrictor, but also acts on the CNS to increase vasopressin production and aldosterone release (salt retention in kidney)

124
Q

Sympathetic NS acts on the RAS and cardiac cycle how?

A
  1. Increases RENIN production. (increases angiotensin II which acts back to increase sympathetic NS,
  2. Increases peripheral resisitance (directly and indirectly via angiotensin II and aldosterone and vasopressin- hypertension and vasoconstriction)
  3. Increases cardiac output
125
Q

What is the sympathetic NS good at bad for?

A

Good: if blood loss e.g. lion bites you- NorA will increase peripheral resistance so channelling the blood to the vital organs and increases cardiac output (tachycardia and positive inotropic) so organs and muscles get more O2 etc. Increased BP and circulating volume of blood.

Bad: HF- body cant distinguish between the two. Peripheral resistance via vasoconstriction and hypertension increases afterload- harder to pump blood around- and increased CO increases hearts blood demand, heart cant cope.
Chronic adrenergic stumulation- myocyte toxicity and arrhythmia.

126
Q

Angiotensin I to II?

A

ACE cleaves off the C terminus

127
Q

Hormone related to sympathetic NS which impacts RAS?

A

NorAdrenaline

128
Q

Trial on ACE inhibitors for heart failure?

A

253 severe heart failure (grade 4) in 1 year mrtality decreased from 60% to 30% with Enalapril.

Ramipril also reduction from 30-20% with patients wiht mild LVD but not heart failure yet. Death and hospitalisation endpoint reduced and death and HF also reduced.

129
Q

Uses for ACE inhibitors?

A

Hypertension
Heart failure
Diabetic nephropathy
(Reduce ACE, reduce Angiotensin II, reduce aldesterone and vasopressin- stop salt and water rention causing hypertension)

130
Q

ACE inhibitor examples?

A

Ramipril, Enalapril etc

131
Q

ACE inhibitor side effects?

A
  1. (Angiotensin II reduction)
    - hypotension
    - acute renal failure (efferent contraction-increases GFR)
    - hyperkalaemia (Na retention)
    - Teratagenic faetal abnormalities.
  2. Related to increased Kinins.
    - allergy reactions anaphalactoid
    - dry cough
    - rash.
132
Q

Why can ACE inhibitors cause anaphalactoid reactions?

A

ACE causes the convertion of Bradykinin into inactive peptides (so if inhibit ACE bradykinin levels increase)

133
Q

Beta blockers trial?

A

with Carvedilol after 1 year 97% survived, vs 90% placebo. And event free suvival als increased as well as hospitalisation decreased.
(HF)

134
Q

Beta blockers are additive with what?

A

ACE Inhibtiors for HF

135
Q

Use of Beta blockers?

A

Ischaemic heart disease (IHD) (angina)
Heart failure and arrhythmia
Hypertension

136
Q

Example of beta blockers?

A

Bisoprolol, carvedilol, metoprolol - That have evidence benefit for HF
also.. atenolol, propranolol (wth no evidence)

137
Q

Which beta blockers are selective/ not?

A

Non-selective= B1/B2 - Propranolol, Nadolol and Carvedilol.
Cardioselective= B1 selective- metaporpolol bisoprolol
(Atenolol half way between)

138
Q

why is cardioselective for Beta blockers a bad term?

A

40% B receptors in the heart are B2 but poor phrase.

Also the beta blockers are on a spectrum, and as the dose increases they often become less selective.

139
Q

Beta blockers side effects?

A

Block B adreno receptors.
Fatigue, headache, sleep disturbance.
Bradycardia, hypotension, cold peripheries (heart slows, BP lowers due to vasoconstriction less to peripheries.)
Erectile dysfunction
Worsen asthma, COPD, PVD and can make heart failure worse if wrong dose.

140
Q

Digoxin for HF?

A

stimulates heart contraction, but no difference in mortalty but decrease in hospitalisation in right dose

141
Q

Ivabradine in HF?

A

If funny current in SAN is blocked by Ivabradine. This slows the SAN down for agina and heart failure.
Death and hospitalisation decreases with HF.

142
Q

Sacubitril/Valsartan in HF?

A

Sacubitril is a neprilysin inhibitor (which increases natriuretic peptides (increase sodium excretion and therefore water- Increase EXV-BP).
Valsartin- angiotensin II blocker,

143
Q

In acute HF what is the response?

A

-Oxygen (can sufficate by drowning- pulmonary oedema)
Diamorphine (heroin)- vasodilator relaxes patient
Nitrates- vasodilation, decreases preload (intravenous)
Loop diuretics IV- vasodilation
Inotropes (if treatable cause)
1. adrenergic agonists (mimics sympathetic NS)
2. PDE III inhibitors- breakdown of CAMP block- increased sympathetic NS.

144
Q

HF drugs?

A
  1. Digoxin
  2. Ivabradine
  3. Sacubitril/Valsartan
  4. Beta blockers (vasodilate)
  5. ACE inhibitors (reduces angiotensin II)
  6. Aldosterone antagonist.

Patients often have all 3- ACE inhibitors, betablockers, Aldosterone antagonists, then digoxin or Ivabradine added.

145
Q

Promise study?

A

40% mortality placebo, increased with milrinone (phosphodiesterase 3 inhibitor that works to increase the heart’s contractility and decrease pulmonary vascular resistance.)

BMS 109 (20 decks)

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