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MoDA > Cardiovascular and Renal > Flashcards

Cardiovascular and Renal Flashcards

1
Q

What is the Fast depolarising phase of the cardiac action potential due to

A

Opening of voltage gated sodium channels

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2
Q

When are voltage gated sodium channels in the heart inactivated

A

They remain in a closed estate until shortly after the membrane returns to its normal resting potential

Until this has happened it is not possible to open the channels again

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3
Q

What is the difference between voltage gated sodium channels in the heart compared to neurons and skeletal muscle

A

In neurons and skeletal muscle of the initial depolarisation needed to gate the sodium channel is produced by the action of a neurotransmitter, whereas in the cardiac cells this depolarisation is provided by pacemaker cells

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4
Q

Describe the structure of voltage gated sodium channel in the brain

How is it different in the heart

What about in electric eel

Therefore?

A

Three subunits α β1 β2

There are only α and β1 in heart

Only α

The α subunit is all that is required for voltage gated sodium channels to show a particular type of behaviour

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5
Q

What happens if you take a brain α subunit from a sodium channel and expressed it in xenopus oocytes

What happens if β1 is coexpressed with the α

A

They produce a current which is somewhat different from that scene in brain neurons

Current produced is virtually identical to that in the brain

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6
Q

What does the β subunits do in Na VG channels (3)

A

Modulate the heating properties of the channel

Regulation of channel expression

Control the way in which the channels are associated with various structural protein elements in the cell

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7
Q

How can the structure of a VG Na+ channel α subunit be described (3)

Which segment is most of interest

A
  • Has roughly 4 homologous domains which each have six transmembrane segments S1–6
  • The regions between the S5 and S6 segments from the extracellular entrance to the channel
  • S6 segment line the channel pore

S4 – it has a charged residue every third position suggesting it is the voltage sensor

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8
Q

What is the peculiar arrangement of amino acids in the ass for segment of the α subunit of the voltage gated sodium channel

A

Has a charge residue every third position (5 to 8 amino acids in each S4 segment)

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9
Q

What kind of experiments we used to determine the function of the S4 segment of the alpha-subunit of the voltage gated sodium channel

A

Site directed mutagenesis

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10
Q

Describe the short intracellular region linking domains III and IV in the α subunit of the VG Na+ channel

What are these important for? How do we know?

A

Contains a group of three hydrophobic amino acids:IFM (Ile, Phe, Met)

They are critical for in activation - thought that III-IV linker acts as a lid to occlude intracellular channel face

Mutation of the IFM residue to QQQ (3 glutamine) results in sodium channels that activate normally but in activate much more slowly and to a lesser extent than wild type

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11
Q

What happens if proteolytic enzymes are exposed to the intracellular face of axons, damaging the intra cellular domains of the alpha-subunit of sodium channels

A

Inactivation is abolished

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12
Q

Why can anaesthetics be used on both sensory neurons and as antidysrhythmic drugs

A

The sodium channels exhibit the same sort of structure

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13
Q

Why are local anaesthetics sometimes called membrane stabilising drugs

A

They inhibit the propagation of action potentials

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14
Q

How do different local anaesthetics Affect different cells

What does this mean

A

Smaller diameter cells are more sensitive to the drug than larger diameter cells

Drugs will at low concentrations block nervous conduction well not affecting muscle action potentials

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15
Q

In a mixed fibre sensory nerve in which order are sensations blocked

What does this correspond to

A

Pain

Cold

Warmth

Touch

Deep pressure

This sequence corresponds to increasing diameters of nerve fibres

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16
Q

Give five ways to administer local anaesthetic

A

Surface Anastasia

Infiltration Anastasia

Nerve block

Epidural Anastasia

Intrathecal Anastasia

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17
Q

How was the mode of action of local anaesthetics on sodium channels studied

A

Using a voltage clamp on a single myelinated nerve from the sciatic nerve of the frog

He used to common local anaesthetics: tetracaine and benzocaine

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18
Q

Describe Hille’s experiments on Na channels with local anaesthetic

How can this be explained

A

Tetracaine inhibited the sodium current much more effectively at PH 8.3 than pH 6.0 whereas benzocaine showed approximately the same degree of inhibition at both pH values

They have different PK8 values: tetracaine has APKÁ of 8.5 so at PH 8.3 approximately 50% of the tetracaine is in its uncharged form

Benzocaine has a PK a value of 2.6 which means that both pH six and 8.3 it is in the uncharged form mostly

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19
Q

What did Hille’s experiments With tetracaine and benzocaine and the voltage gated sodium channel mean

How did he resolve this

A

Either the on charge form of the drugs are the active form or the drug has to be in its on charge form to gain access to site of action where it might act in either its charge or on charge form

By using quaternary local anaesthetics named our a C – 421 and QX – 314. This showed no noticeable anaesthetic effect when applied to the median bathing in the exam but produced appreciable anaesthesia when they were injected into the cell

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20
Q

What were the conclusions of Hille’s experiments (3)

A

Local anaesthetics act on the Internet surface of the voltage gated sodium channel

Drugs need to be in charge to pass across the cell membrane – the more hydrophobic the drug the better it is at crossing the membrane

The charge form of the drug is the form that interacts with the channel to produce the anaesthetic effect

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21
Q

What does quaternary local anaesthetics mean

A

Permanently charged

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22
Q

What did further experiments with QX – 314 reveal

A

It is necessary for the channel to be open for the majority of the anaesthetic effect to be initiated. The more often the child opens the more likely it is to be blocked by anaesthetic

Use dependence

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23
Q

How do local anaesthetics act now

A

Gain access to the channel in the hydrophobic, and charged form

Once inside the cell a proportion of the anaesthetic drug becomes charged and thus hydrophilic which then interacts with the intracellular part of the channel

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24
Q

Is local anaesthetic blocking of sodium channels always use dependent

A

No! the hydrophobic form of the drug can gain access to the channel as they pass through the cell membrane adjacent to the channel

That the lodge in the channel and exert some anaesthetic action and the channels do not need to be open for this

There does hydrophilic and hydrophobic pathways for local anaesthetics to act on sodium channels

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25
Q

During the course of an action potential the membrane depolarises from -80mV to 20 mV. How many sodium channels remain inactivated when the membrane returns to 80mV?

How can this inactivation be completely abolished

A

30-50% are inactivated

By driving the membrane potential beyond -80 mV

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26
Q

Describe the experiment of Hille when testing sodium channel activation at very negative voltages

A

Cell is clamped at -83 and then stepped rapidly to values from -53 2+67 with periods of -83 between test pulses

Some specimens have pulses that are preceded by 50 ms peoples of -143 which reactivate all the sodium channels

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27
Q

What do site directed mutagenesis experiments show when directed at a sequence of amino acids at the cytoplasmic end of the S6 region of domain IV?

A

That it confers local anaesthetic sensitivity and voltage gated sodium channels

Inhibitors of voltage gated calcium channels act on the analogous region in these proteins

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28
Q

Name three toxins that act on the voltage gated sodium channel

A

Tetrodotoxin

Batrachotoxin

Scorpion toxins

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29
Q

Describe tetrodotoxin

Name a related toxin

A

Highly selective reversible blocker of neuronal voltage gated sodium channels.

Tetrodotoxin binds to a ring of COOH residues at the mouth of the pore and these residues correspond to Glu387 in the S6 segment.

Saxitoxin

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30
Q

Mutations in which part of the voltage gated sodium channel leads to loss of tetrodotoxin (TTX) binding

A

Glu387 in the S6 segment of domain I

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31
Q

True or false

TTX is considerably less effective on cardiac sodium channels

Explain

A

True

It is blocked only by micromolar concentrations of the toxin whilst the neuronal and skeletal channels require only nanomole quantities

Segment S6 -Cardiac has Cys at 373 while other tissues have Phe or Tyr here. If you replace cys with Phe or Tyr In cardiac you confer TTX sensitivity

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32
Q

Where does batrachotoxin come from

What about TTX and saxitoxin

A

The skin of a Colombian tree frog

TTX- puffer fish organs
Saxitoxin - marine dinoflagellates

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33
Q

Describe the action of batrachotoxin!

A

It is an alkaloid and membrane payment

Acts on the intracellular portions of the channel to prevent in activation and to move the activation potential to more negative potentials so the channels open far more readily than in the absence of the toxin

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34
Q

Which toxins act in the same way as batrachotoxin

A

Aconitine and veratridine (plant alkaloids) - can cause

Pyrethrin insecticides and DDT act similarly in insects

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35
Q

What do you scorpion toxins contain

A

A cocktail of toxins that affect various ion channels and the exact composition of venom varies from species to species

Alpha scorpion toxin is a polypeptide that acts from the outside of the voltage gated sodium channel. It inhibits in activation and act co-operatively with batrachotoxin open the channel almost permanently

its binding is voltage dependent and is enhanced by batrachotoxin

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36
Q

How is the VG Ca2+ channel similar to the Na+ channel in the heart

A

Has a large protein associated with several accessory proteins (α2, δ and β subunits)

These subunits enhance channel trafficking and regulate the expression of Ca2+ channels at the PM
They also influence α1 and thus the conductive properties of the channel

α1 is v similar to VG Na+ - Shows voltage sensing, selectivity and inactivation characteristics

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37
Q

How are the α2 and δ subunits of the cardiac Ca VG channel related

A

α2 and δ are linked by a disulphide bridge but both are from the same gene

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38
Q

What are the principal drugs that act on voltage gated calcium channels in the heart? Give eg (3)

Categorise then

A

Dihydropyridines (eg nifedipine) and non-dihydropyridines:

Phenylalkylamines (verapamil)

Benzothiazepines (diltiazem)

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39
Q

What are the two types of voltage gated calcium channels which are of direct relevance in the heart and cardiovascular system

A

L (long) and T (transient) type

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40
Q

Compare the amount of depolarisation required to activate L and T type calcium channels

A

L: depolarisation of >30mV
T: 10-20 mV

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41
Q

Where are L type channels found

What do they do

A

In virtually all excitable cells

Trigger excitation contraction coupling in cardiac, smooth and skeletal muscle as well as control hormone release from endocrine cells and some neuronal transmitter release

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42
Q

What is the single channel conductance of L-type calcium channels in the heart

How long do they stay open for and inactivate

A

22-27pS

relatively long time and do not inactivate rapidly do so slowly

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43
Q

How is L-type calcium channel activity enhanced in cardiac cells

A

Via the action of adrenaline and noradrenaline which lead to phosphorylation of the channels

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44
Q

Which channel type do calcium channel blocking drugs of the cardiovascular system target

A

L type

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45
Q

Describe the opening and in activation of T type channels

What is the channel conductance

A

Open transiently and show rapid inactivation

8pS

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46
Q

What are LVA Ca2+ channels

A

Low voltage activated calcium channels (T type)

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47
Q

Where do T type channels occur

A

Occur together with L type channels in nodal pacemaker tissues in the heart

Triggering of T type channels can be sufficient to depolarise the cell enough to activate L type channels

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48
Q

Generally what happens if potassium channel is open in normal cell

What type of potassium channel do cardiac and other excitable cells have

A

Potassium flows out of the cell making the membrane potential more negative

Voltage gated potassium channels which open slowly on depolarisation and the current they carry leads to the restoration of the membrane potential

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49
Q

What determines the resting membrane potential in atrial and ventricular cells

A

The membrane having high permeability to K+ (ie Is dependent on the activity of the potassium channel)

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50
Q

What is the dual role of potassium channels in the heart

A

Repolarisation of the sale at the end of an action potential

Stabilisation and modification of the resting cell membrane potential in the atria and ventricles

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51
Q

What is the shaker mutant a polymorphism of

A

A voltage gated potassium channel isolated in fruit flies

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52
Q

Describe the Shaker family voltage gated potassium channels in the heart

A

Six transmembrane segments, familiar to sodium channels, but only show a single group of the six segments, compared with the four of the sodium channels

Four voltage gated chassis and channel proteins combine to give a functional channel

Every third residue in the S4 segment is positively charged and mutagenesis experiments suggest that this form is a voltage sensor

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53
Q

Both potassium and sodium voltage gated channels have six transmembrane segments but potassium channels only show a single group of the six segments compared with the four of the sodium channels. What does this suggest

A

Voltage gated sodium channels arose from the potassium channel gene through gene duplication

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54
Q

What are the 2 types of inactivation showed by VG K+ channels

A

N-type and C type

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55
Q

Describe N type inactivation

A

“Ball and chain inactivation”

N terminus of the protein forms a ball which is sucked into the pore, occluding it as the result of electrostatic changes associated with depolarisation

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56
Q

Describe C type inactivation

A

Slower inactivation of K+ channels

Result of movement of residues near the extracellular surface of the pore

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57
Q

Which K+ current is most important for the maintenance of the cardiomyocyte resting potential

A

Ik1 current (inward rectifying)

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58
Q

What happens if all the channels conducting the Ik1 current are open?

A

potassium is free to move across the membrane throughout the action potential

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59
Q

How much time do cardiac cells spend in depolarisation?

Why is this important?

A

50%

without some protection theey would lose lots of K+ through the resting potential type K+ channels

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60
Q

When is the outward driving force highest for K+ during the AP?

Why do we need to know this/

A

during depolarisation

as cardiac myocytes spend 50% of their time depolarised, inward rectification is needed to prevent mass K+ loss

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61
Q

How many transmembrane domains do channels carrying the Ik1 current have?

What family do these channels belong to?

A

2

Kir

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62
Q

Describe how Kir channels work in the heart

A

conduct inward K+ v effectively at hyperpolarised potentials but close at depolarised potentials, preventing an outward K+ current

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63
Q

True or false:

inward K+ rectification is due to intracellular Mg2+ lodging in the pore

A

True but it is not solely due to Mg2+ - intracellular polyamines (esp. spermine) are of great importance

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64
Q

What is the valency of spermine

A

tetravalent

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65
Q

Is inward rectification only in the heart?

A

no they are common to many types of K+ channels in many tissues (some show both VG and inward rectification)

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66
Q

Other than the heart, name an organ which shows K+ inward rectification and state the reason for it being present

A

liver, kidney

purpose is unclear as these tissues never depolarise

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67
Q

Is the Kir channels carrying Ik1 the only inward K+ rectification in the heart?

A

No there are channels that carry currents such as I(K-ACh) and I(K-ATP) which are part of the Kir family

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68
Q

Describe the I(K-ACh) current (3)

A

sensitive to ACh

mediated by M2 receptors

hyperpolarises cardiocytes

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69
Q

Which channel carries the I(K-ACh) current

A

Kir3.1
or
HGIRK1 (Human G-protein-activated Inward Rectifying K+ Channel)

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70
Q

Describe the I(K-ATP) current

A

carried by ATP-sensitive K+ channels

close in presence of high [ATP]i (depolarising) and open when [ATP] falls (hyperpolarising)

may protect the heart from ischaemia

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71
Q

How are K(ATP) channels used pharmacologically?

A

influenced by sulphonylurea drugs to stimulate insulin secretion in T2 DM

present in vascular smooth muscle so targeted for hypertension

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72
Q

How does resting potential differ across the heart?

A

SNV and AVN: -60mV

Ventricles: -80mV

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73
Q

How are I(K-ACh) channels activated

A

M2 activated and βγ subunits couple directly to the channel, opening it

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74
Q

What factors affect the shape of the different cardiac APs

A

resting potential

expression of channel proteins

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75
Q

Give a cause of SADS

A

Long QT syndrome - heart suddnely goes into ventricular fibrillation

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76
Q

Give some conditions that SADS patients can have

A

hypertrophic cardiomyopathy
dilated cardiomyopathy
long QT syndrome

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77
Q

Why may the QT interval be extended

A

pharmacologically by some antibiotics (eg Clarithromycin) and antipsychotics

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78
Q

How do channels producing the If behave

A

similar to inward rectifiers - open on hyperpolarisation and close on depolarisation

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79
Q

How do If channels differ from Kir channels

A

channels for If are equally permeable to K+ as Na+

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80
Q

channels for If are equally permeable to K+ as Na+. What does this mean upon hyperpolarisation of the cell?

A

Na+ begins to enter, leading to a slow depolarisation, which will cause VG Na+ to open when the threshold is reached

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81
Q

What us the main difference bwteen pacemaker cells and myocytes

A

the presence of the If and the absence of VG Na+ current

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82
Q

What do Ca2+ channels do in the cardiac AP

A

L and T type channels generate the peak if the nodal AP

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83
Q

What do VG K+ channels contribute to the cardiac AP

A

Repolarisation

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84
Q

What is the name of the channels underlying the If

A

HCN

Hyperpolarisation-activated and Cyclic Nucleotide gated channels

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85
Q

what is the structure of HCN channels

How are they activated specifically?

A

the familiar S1-6 structure with a voltage sensing S4 segment and a selectivity pore between S5 and S6

activated directly by cAMP (rather than the previous cAMP mediated PKA phosphorylation)

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86
Q

Where is HCN1 present

A

brain and heart

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87
Q

what are HCN2 and HCN4

A

HCN subunits most abundantly expressed in the heart

HCN2- throughout the heart; HCN4- Purkinje fibres and pacemaker regions

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88
Q

What does SNS action do the heart

A

positive inotropic and chronotropic action

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89
Q

What must any change to heart rate be mediated by

A

the potentials produced by the SAN

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90
Q

How do catecholamines affect rhe heart `

ACh?

A

increase rate of production of pacemaker potentials

ACh reduces the rate

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91
Q

How does beta AR stimulation affect the heart

What opposes this?

A

leads to a rise in [cAMP]i

M2 receptor stimulation

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92
Q

How are beta ARs and muscarinic receptors distributed in the heart?

A

beta ARs are on nodal cells and on the ventricular cells

muscarinic are mainly confined to the nodes

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93
Q

What is an increase in L and T type Ca2+ currents mediated by

How can this be mimicked? Blocked?

A

cAMP

administration of adrenaline or isoprenaline
blocked by propranolol (non specific beta blocker) or atenolol (specific beta 1 blocker)

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94
Q

In the heart, beta 1 ARs are coupled to Gs, leading to a rise in cAMP. Which Ca2+ channel is this important for?

A

L type - modulates pacemaker potential and enhances Ca2+ entry into cells for excitation-contraction coupling

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95
Q

How fast is the time-course of the effect of stimulation of Ca2+
currents by ß1
receptor agonists or by
addition of cAMP?

Is the reversal of this effect comparable?

A

quite slow - latent period of 5s and then takes 30s for current to reach max.

yes - reversal is also slow

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96
Q

Why is the stimulation of cardiac Ca2+ channels slow?

A

must be phosphorylated by PKA so whole process involves cAMP and then PKA stimulation. - much slower than ligand gated ion channel

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97
Q

How can you mimic the effect of beta1 stimulation?

A

using cholera toxin (stimulates G protein) or forskolin (stimulates AC)

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98
Q

What covalent modification happens to SERCA2 during the cardiac AP? Name another molecule that also undergoes this modification

A

PKA phosphorylates SERCA2 and phospholamban

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99
Q

How do catecholamines affect the If

A

shift the voltage at which If is activated to a more positive value

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100
Q

How do cAMP and isoprenaline affect delayed rectifying K+ channels

A

enhances repolarisation, shortening the AP having a positive chronotropic effect

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101
Q

How do M2 receptors affect cAMP

A

inhibit its formation so has the reverse effect of catacholamines

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102
Q

True or false

Over activation of M2 can stop the heart

A

true - such as in excessive vagal simulation

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103
Q

How does M2 receptor activation affect Ca2+ in the heart

A

Ca2+ currents are reduced, leading to a reduced rate but NOT reduced contractility because M2 are largely confined to the nodes

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104
Q

How does M2 stimultaion affect If

A

the potential at which If is activated is made more negative, meaning pacemaker produces more widely spaced potentials

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105
Q

Is the I(K-ACh) current influenced by M2

A

yes - directly

stimulation hyperpolarises the cell, making it more difficult to elicit APs

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106
Q

What is an ectopic pacemaker

A

also called an ectopic focus - this is a pacemaker at a site other than the SAN

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107
Q

What happens when waves of depolarisation in the heart collide?

Is this a bad thing?

A

they extinguish each other

these extinctions are important for normal cardiac function

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108
Q

Why may electrical organisation problems arise in the heart ?

A

SAN not operating properly, allowing ectopic foci to form

myocardium is damaged, slowing conduction velocity

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109
Q

What is the issue with conduction organization if the myocardium is damaged?

A

slowed velocity means impulses are no longer coordinated .

Inappropriate excitation occurs as an impulse might excite a tissue that would normally be refractory

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110
Q

what is the commonest reason for conductive abnormalities

A

myocardial infarction/ heart attack

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111
Q

What happens to conduction in a heart attack

A

part of the myocardium becomes hypoxic and stops operating correctly (for both conduction and contraction).
Tissue may be replaced by connective tissue which is non conductive

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112
Q

What happens in angina pectoris

A

myocardium becomes ischaemic and cannot operate efficiently but all tissue can conduct

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113
Q

Describe Wolff-Parkinson-White syndrome

A 
congential abnormal (extra) conducting fibres 
accelerates transmission from atria to ventricles
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114
Q

Can dysrhythmias be caused by mutations in ion channels

A

yes - eg Long QT Syndrome - more than 150 different mutations haev been indentified in seven LQT genes

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115
Q

Which 3 gene mutations account for 95% of identified mutations causing Long QT syndrome?

What can mutations in these genes do?

A

LQT1 (43%)
LQT2 (45%)
LQT3 (7%)

modify cardiac AP and voltage gradient in conduction tissues especially at ventricular level. Environment is also important

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116
Q

What is important to note about the Vaughan Williams classification of antidysrhythmic drugs

A

they are based on the effect of the drug not the type of drug itself

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117
Q

What are the different classes of antidysrhythmic drugs according to Vaughan Williams

A

Class I: block VG Na+ channels
Class II: SNS blockers
Class III: Prolong AP and refractory period
Class IV: Ca2+ channel blocker which reduces Ca2+ entry

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118
Q

Give an example of each of the Vaughan Williams antidysrhythmic drug classes?

A 
IA: quinidine, procainamide
IB: Lidocaine
IC: flecainide
II: propranolol, atenolol
III: amiodarone
IV: verapamil
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119
Q

Describe Class I antidysrhythmic drugs

A

block VG Na+ channels
subdivided into 3 classes:

IA: increase AP duration, with intermediate rate of diss/association

IB: decreased AP duration with v fast association and dissociation

IC: No effect on AP but v slow association and dissociation

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120
Q

Which antidysrhythmic drugs block Ca2+ channels

A

Class IV eg Verapamil

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121
Q

What is cardiac failure?

A

the heart failing to maintain an adequate circulation for sufficient tissue perfusion

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122
Q

What is the range of volumes the heart can pump in a healthy condition

A

2-25 litres per minute

Normal is 5L/min

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123
Q

If the right side of the heart is failing, how does it manifest?

A

Peripheral oedema and ascites (fluid forced out of the liver into the abdominal cavity)

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124
Q

What happens in left heart failure?

A

pulmonary oedema, leading to cardiogenic shock

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125
Q

How is the kidney involved in heart failure

A

insufficient perfusion leads to renin secretion and thus fluid retention, increasing MSFP

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126
Q

Which side heart failure leads to cyanosis? What other symptoms are common in this type?

A

both

breathlessness and fatigue

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127
Q

Does heart failure develop rapidly?

A

It can do in myocardial infarction but can also develop slowly after excessive demands on the heart

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128
Q

Give 11 reasons for excessive demands being put on the heart

A 
Dysrhythmias (which inhibit normal cardiac function)
• Coronary artery disease
• Past myocardial infarction
• Hypertension
• Abnormal heart valves
• Heart muscle disease (e.g. dilated cardiomyopathy, hypertrophic cardiomyopathy) or
inflammation (myocarditis)
• Congenital heart defects
• Severe lung disease
• Diabetes
• Hyperthyroidism
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129
Q

What are the 4 classes of cardiac failure according to the NY Heart Association

A

Class1: Minimal dyspnoea (except after moderate exercise)
Class 2: Dyspnoea while walking on the flat
Class 3: Dyspnoea on getting in or out of bed
Class 4: Dyspnoea while lying in bed

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130
Q

What is the prognosis for people with Class 4 heart failure

A

very poor

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131
Q

What is drug treatment for heart failure based upon?

A

increasing contractility
increasing rate
reducing heart’s work load(by reducing MSFP)

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132
Q

Give the different types of drugs that can be used for heart failure (5)

A 
cardiac glycosides
Dobutamine (ß1  agonists) for rapid effect in acute cases
Beta-blockers
Inodilators
ACE inhibitors
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133
Q

Where does the cardiac glycoside digoxin come from

A

foxglove extract

been used for 200 years

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134
Q

What are cardiac glycosides more commonly used for now?

A

as antidysrhythmic drugs

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135
Q

What is ouabain?

A

a very potent cardiac glycoside that is not used clinically

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136
Q

What do cardiac glycosides do

A

inhibit Na+/K+ ATPase

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137
Q

What happens to the Ca2+ in the heart cells during diastole?

How is this achieved?

A

Ca2+ leaves to bring about relaxation

NCX

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138
Q

Why is the Na+/K+ pump important for Ca2+ removal in cardiomyocytes?

A

Na+ Pump creates a conc gradient that the NCX uses to extrude Ca2+

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139
Q

What is the stoichiometry of NCX

A

3 Na+ in: 1 Ca2+ out

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140
Q

How do cardiac glycosides affect [Na+]

A

increase [Na+]i from 1mM to 1.5mM

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141
Q

What, in cardiomyocytes, does [Ca2+]in depend on?

A

[Na+]in to the third power - a small change in intracellular Na+ wll produce relatively large charge in intracellular Ca2+

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142
Q

Does the number of Na+ pumps change in disease?

A

Yes the number of pumps deceases in ischaemia

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143
Q

Should you use ß1

agonist to treat heart failure (3)

A

NO - while it does have a positive inotropic effect, this increases O2 demand.
They also increase rate, revealing dysrhythmias
may also precipitate/ potentiate hypertension

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144
Q

Are ß1

agonists ever used to treat heart failure?

A

yes
Dobutamine (ßl
-selective analogue of dopamine) is used for acute failure as its positive inotropic effect&raquo_space; chronotropic

used for shock or to improve CO after open heart surgery or in heart failure in absence of hypertension

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145
Q

Why are ß blockers used in heart failure?

A

homeostatic response is to increase SNS output but this gradually decreases heart function so blocking this is important in chronic heart failure

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146
Q

Where does the key to the potentially harmful effect of chronic adrenergic stimulation on myocardial function lie?

A

desensitization and downregulation

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147
Q

What is the normal ratio of ARs in the heart? ( ß1:ß2: á1)

How does this change in heart failure

How does tis affect SNS output

A

70: 20:10%
50: 25:25%

(ß1
receptors are
disproportionately downregulated and á1
receptors are upregulated)

SNS output increases but this can lead to overstimulation and apoptosis of myocytes

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148
Q

Describe experiment where the toxicity of excess NA was tested

A

1990s - exposed mammalian cardiomyocytes to catecholamines, resulted in cell death

Stimulation with NA resulted in spontaneous contractions and then hypercontraction and cell death

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149
Q

How do different AR blockers affect heart health in cardiac failure

A

á-adrenoceptor antagonist (phentolamine) - slight blocking action on the toxic effects of NA

beta antagonist (propranolol) led to greater
attenuation
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150
Q

Which AR antagonists are used in heart failure

Name 2

A

3rd generation ß1 blockers

eg bisoprolol and carvedilol

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151
Q

What must you be careful of when using beta blockers in heart failure

A

they must be carefully titrated due to the risk of overinhibition

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152
Q

What are inodilators

A

inotropic vasodilators

ie phosphodiesterase inhibitors

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153
Q

What does PDE do

Therefore, what do inodilators do to the levels of molecules in the cell

A

catalyzes breakdown of cAMP

increases cAMP levels, mimicking effects of ß-receptor stimulation

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154
Q

True or false:

Inodilators can lead to arrhythmias

A

True because they mimic beta AR stimulation

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155
Q

Name an inhibitor drug for each of the 5 types of PDE

A 
I: phenothiazines
II: N/A
III: milrinone *
IV: rolipram
V: dipyridamole*, sildenafil *
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156
Q

What kind of drug is sildenafil?

A

Type V PDE inhibitor

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157
Q

Which inodilator is most commonly used in heart failure?

What type of PDE does this inhibit?

What is a caveat of using this drug?

A

milrinone

PDE Type III

it has limited use because can cause dysrhythmias - limited to short term treatment of severe heart failure that is unresponsive to conventional therapy

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158
Q

How do inodilators cause vasodilation?

What is the benefit of this?

A

in smooth muscle, increased [cAMP], from PDE III inhibition, leads to vasodilation

decreases afterload on heart

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159
Q

What durg type are non selective PDE inhibitors?

A

methylxanthines (eg caffeine and theophylline)

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160
Q

Methylxanthines are non selective PDE inhibitors. What else do they do?

What does the combination of these effects lead to?

A

they are also adenosine A1 and 2 antagonists and at high conc. cause release of Ca2+ from intracellular stores

positive inotropic and chronotropic effects, and a tendency to give rise to dysrhythmias

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161
Q

Which of the effects of methylxanthines are most important in the CNS ?

A

adenosine receptor antagonism

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162
Q

Which inodilator has revolutionized canine dilated cardiomyopathy in Dobermanns ?

What class of drug is this drug part of?

A

Pimobendan

‘calcium sensitizers’

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163
Q

What do Ca sensitisers do?

A

sensitise and increase cardiac Ca2+ binding efficiency to troponin without increased energy consumption

also inhibit PDE III so cause vasodilation

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164
Q

name a calcium sensitiser in human clinical practice

A

levosimendan (not licensed in the UK)

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165
Q

Name a PDE used to treat mental illness

A

phenothiazines

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166
Q

What is the muscle specific SR Ca2+ ATPase that leads to relaxation

A

SERCA2

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167
Q

What is phospholamban

A

an endogenous muscle specific SERCA2 inhibitor

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168
Q

What is the key regulator of the SERCA2/ phospholamban inhibitor

A

the SNS via beta AR activation and PKA

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169
Q

How does PKA affect the SERCA2/ phospholamban system

A

phosphorylates ryanodine, SERCA2, and phospholamban, allowing for intracellular Ca2+ transients with higher ampiltudes and and faster reuptake

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170
Q

What does PKA’s phosphorylation of phospholamban do

A

promotes dissociation of phospholamban from SERCA2, relieving inhibition, allowing faster reuptake

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171
Q

Reduced Ca2+
transient amplitudes and slowed rates of SR Ca2+
re-uptake have been observed in
cardiac muscle cells from failing human hearts. What does this mean for future therapy?

A

correcting Ca2+ transient by manipulating components phosphorylated by PKA may help recover contractility

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172
Q

The gene for which protein has been tested as a gene therapy treating heatr failure?

A

phospholamban

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173
Q

Describe the experiments assessing validity of phospholamban gene therapy for heart failure (2)

Result?

A

knock out mice or viral delivery of antisense phospholamban to cardiac cells

improved calcium handling and contraction but similar experiments were less successful

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174
Q

Describe a human example of depleted phospholamban

A

two human families were identified who have null-like polymorphisms
in the human phospholamban gene (so rather analogous to the knockout mice), and the affected
members of the families show dilated cardiomyopathy, requiring heart transplantation as young
adults.

Phospholamban is not a good target

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175
Q

Describe the experiment assessing the effect of gene therapy on SERCA2 for treating dysrhythmia

What was the effect

A

disrhythmia was reversed even when catecholamines were used to induce dysrhythmia

When failing heat cells were transfected with the SERCA2
gene in vitro the results revealed that SR Ca2+
levels were restored, RyR phosphorylation was
normalised and total SR leak was reduced, producing beneficial positive inotropic and lusitropic effects

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176
Q

What does lusitropic mean

A

producing cardiac relaxation

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177
Q

How are viruses used in possible SERCA2 gene therapies

A

use of adeno-associated virus vectors to introduce

the gene for expression

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178
Q

What kind of therapy is very useful after a myocardial infarction?

What does this decrease the incidence of?

A

fibrinolytic therapy

arrhythmia

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179
Q

What is streptokinase

A

a 47kDa protein formed by haemolytic streptococci

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180
Q

Describe the action of streptokinase

A

binds plasminogen activator leading to the generation of plasmin and thus the degradation of fibrin in clots

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181
Q

What is plasmin

A

a protease hydrolysing Arg-Lys

bonds

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182
Q

which protein does plasmin degrade>?

What else does it break down

A

fibrin

clotting factors II, V and VII

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183
Q

What is alteplase

why is it particularly beneficial

A

recombinant human tissue plasminogen activator

has greater activity on plasminogen bound to fibrin in clots, thus localizing their action

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184
Q

Why is low dose aspirin used in a heart attack

What is it often combined with

A

prevents further thrombosis

clopidogrel

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185
Q

Describe the action of clopidogrel

A

inhibits platelet aggregation by inhibiting the

binding of ADP to its receptor on platelets

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186
Q

Why can’t clopidogrel be used in everyone

A

it is a prodrug so metabolisation in the liver is required for activation

people with 2 non-functioning copies of the gene for the cytochrome P450 that activates clopidogrel cannot activate clopidogrel

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187
Q

What is the name of the gene that encodes the cytochrome that activates clopidogrel

What is this type of cytochrome called

A

CYP2C19

cytochrome P450

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188
Q

In patients with 2 non functional cytochrome P450 genes, what is combined with aspirin after a heart attack

A

ticagrelor (an ADP inhibitor)

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189
Q

Which receptor is needed for fibrinogen binding between platelets? Which drugs target these? Give an example

A

glycoprotein IIb/IIIa receptor

aIIb/b3 integrin antagonists

Eptifibatide

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190
Q

Describe Eptifibatide

A

cyclic heptapeptide inhibitor of the glycoprotein IIb/IIIa receptor

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191
Q

Other than eptifibatide, give 2 exmaples of aIIb/b3 integrin inhibitors

A

tirofiban - a non peptide inhibitor which can be used like heparin

Abciximab - monoclonal antibody against the receptor
- also binds to vitronectin receptor on platelets, endothelial cells adn vascular smooth muscle

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192
Q

Which drug tends to be used with coronary angioplasty for coronary artery thrombosis

A

Abciximab

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193
Q

What is tirofiban used for

A

prevention of myocardial infarction in patients with unstable angina or in patients who have recently suffered certain types of myocardial infarction (eg if identified by ECG)

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194
Q

What process is vitronectin involved in

A

cell adhesion and haemostasis

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195
Q

What is heparin

A

a naturalluy occurring anticoagulant produced by basophils and mast cells

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196
Q

Describe the action of heparin

A

binds antithrombin III causing a conformational change, exposing its active site

Activated antithrombin III then inactivates thrombin and other proteases involved in clotting, eg Xa

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197
Q

What is heparin used for

A

unstable angina and after an MI (like tirofiban)

also useful in deep vein thrombosis and as a prophylactic drug to prevent clot formation during/after surgery

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198
Q

Describe a drug class similar to heparin

A

low Mr heparins

considered distinct from heparin

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199
Q

Why are low molecular weight heparins considered distinct from heparin (3)

A

their wider
application, subcutaneous route of admininstration and more predictable pharmacokinetics
(so are easier to use)

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200
Q

What is an undesirable effect of heparin

A

heparin induced thrombocytopenia as a development of low platelet count

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201
Q

How must heparin be administered

A

by injection

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202
Q

how can warfarin be administered

What does it do

A

orally

inhibits clotting

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203
Q

Give the mechanics of warfarin action (there are 7 molcules affected)

A

inhibits synthesis of clotting factors II, VII, IX, and X

inhibits synthesis of regulatory factors protein C, S and Z

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204
Q

Who is warfarin given to (3)

A

patients with increased tendency for thrombosis or can used used as prophylaxis to guard against reoccurrence in those who already formed a clot that required earlier treatment

prevents clot formation in prosthetic heart valves

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205
Q

Why is dosing of warfarin comlicated

A

t it interacts with many commonly used drugs and other chemicals that may be
present various foods and drinks. These interactions may enhance or reduce warfarin’s
anticoagulation effect

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206
Q

Which anticoagulant can be used as a rodenticide

A

warfarin

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207
Q

Why is warfarin a better rodenticide than other bait based pesticides?

What is a drawback of warfarin?

A

while warfarin carries the danger of accidental poisoning of other animals, other bait based pesticides can be more toxic to non rat species

rats are becoming resistant

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208
Q

Which thrombin inhibitor is used in patients with atrial fibrillation and one other risk factor for a stroke

A

dabigatran

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209
Q

Why is dabigatran used to treat atrial fibrillation

A

this condition can lead to clot development/

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210
Q

How can dabigatran be used in the short term

A

prophylactically to prevent thromboembolism in patients s who have had
recent knee or hip replacement surgery (for example, clots can develop after surgery and be
carried to the lungs to cause pulmonary embolism - which is serious).

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211
Q

Which clotting factor for which a whole set of drugs is named

Give 3 examples

A

Xa

these inhibit Xa directly

rivaroXaban
apiXaban
edoXaban

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212
Q

Name an indirect inhibitor of Xa

What is it used to treat

A

Fondaparinux

acute coronary syndromes

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213
Q

What is argatroban

Which patients is it used in

A

synthetic direct thrombin inhibitor - this is used if patients suffer from HIT

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214
Q

What is bivalirudin

A

a hirudin analogue

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215
Q

What is hirudin

A

thrombin inhibitor found in saliva of the medicinal leech

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216
Q

What kind of drug is danaparoid

Which patients is it used in?

A

an indirect inactivator of Factor Xa and a direct inhibitor of
thrombin activation of Factor IX

Mainly used in patients who have had HIT

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217
Q

What can excessive clot lysis lead to

How can this be treated

A

severe bleeding

with tranexamic acid (TXA) which competitively inhibits plasminogen activation

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218
Q

Other than excessive clot lysis, when may tranexamic acid be used?

A

to suppress bleeding seen in traumatic injury or post partum

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219
Q

Which part of the LoH is impermeable to water?

A

thick ascending limb

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220
Q

What do diuretics do

What is the effect

A

increase urine output

reduce ECF volume

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221
Q

True or false

All diuretics promote natriuresis

A

true - they all increase Na+ excretion

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222
Q

What is the difference between diuresis that occurs after drinking larger amounts of liquid and taking a diuretic drug

A

Diuretic drugs produce an increase in the

excretion of both solutes and water.

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223
Q

What is the way the kindey can activately reabsorb K+ in the DCT and collecting duct

A

K+/H+ ATPase

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224
Q

What are loop diuretics

AKA?

eg?

A

diuretics that act on the LoH

AKA high ceiling diuretics

furosemide and bumetanide

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225
Q

Why are they called high ceiling diuretics

A

they have the capacity to cause a very high rate of diuresis (up to 4 litres/day)

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226
Q

What type of drug are furosemide and bumetanide

A

sulphonamides - a type of loop diuretic

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227
Q

How were sulphonamides developed

A

an early observation that sulphanilamide caused alkalinisation of the urine and mild diuresis. Modification of
sulphonamide structure produced (in turn) carbonic anhydrase inhibitors, thiazides and loop
diuretics, each with a different mode of action.

228
Q

Describe the action of furosemide

A

Blocks NKCC2 of the thick ascending limb of the LoH

229
Q

How does the [loop diuretic] differ from the plasma to the thick ascending limb?

A

10-30x stronger in the ascending limb because it is actively secreted into the proximal tubule

230
Q

True or false

Loop diuretics only affect the NKCC in the nephron

A

false

also weakly inhibits carbonic anhydrase

231
Q

At peak activity, how much of the filtrate can loop diuretics cause to be excreted?

Does this value change?

A

15-25%

On repeated administration the effect is
reduced because the decrease in extracellular fluid volume leads to enhanced reabsorption in
tubules

232
Q

In which emergency condition are loop diuretics particularly useful

A

acute heart failure

because it can lead to such a massive reduction in ECF

233
Q

How long does furosemide take to act if administered IV

How does an oral dose differ?

A

10 mins

extended to 1-1.5 hours

234
Q

True or false

The diuretic effect of furosemide is the most important in acute heart failure

A

false

Quickly causes vasodilation which rapidly decreases RAP

235
Q

How does the vasodilator effect of furosemide aid the effect on the nephron

A

increases renal blood flow without changing GFR (decreases the fraction of the blood flow that is filtered at the glomerulus)

236
Q

Give 4 potential problems with loop diuretics

A

hypokalaemia

concurrent alkalosis

Ca2+ and Mg2+ loss

Uric acid excretion is decreased

237
Q

How can loop diuretics lead to hypokalaemia

A

continued administration means the increased Na+ load in the distal tubule results in increased K+ loss

238
Q

How can hypokalaemia from loop diuretics be avoided

A

K+ can be replaced by exogenous short term K+
-releasing compounds

or loop diuretics can be given with K+-sparing diuretics

239
Q

why can concurrent metabolic alkalosis occur because of loop diuretics

A

enhanced Na+/H+ exchanger activity + increased synthesis of NH3
and secretion of NH4+
leads to increased H+ in the filtrate, which is then excreted

240
Q

Where are Ca2+ and Mg2+ usually absorbed?

Why is their loss increased after taking loop diuretics

A

PCT usually absorbs 80%

mechanism is unknown

241
Q

What does the decreased uric acid excretion lead to while taking loop diuretics

A

gout

242
Q

What do the symptoms of gout arise from

A

xs production of purines, leading to formation of sodium urate crystals in synovial tissue (esp in joints)

243
Q

What is used to treat gout? What is the drug mechanism?

A

probenecid

competes for same carrier as uric acid in PCT, inhibiting uric acid reabsorption

244
Q

What are the commonest Thiazide diuretics

A

hydrochlorothiazide

Bendroflumethiazide

245
Q

Which of the action s of Thiazide diuretics is the same as loop diuretics (2)

A

inhibition of CA

vasodilation

246
Q

What do Thiazide diuretics do overall

A

inhibit formatuion of dilute urine but not a concentrated urine

247
Q

Where is the site of action of thiazide diuretics

A

thick ascending limb or in the distal tubule

248
Q

What is the mechanism of thiazide diuretic action in the DCT?

How was this discovered?

A

blocking Na+/Cl- cotransporter, by blocking Cl- site

investigation of analogous transporter in apical membrane of urinary bladder of the winter fish - blocked by hydrochlorothiazide but not by furosemide or amiloride

249
Q

Describe the hypotensive effects of thiazide diuretics when given for hypertension

A

initially decrease BP from diuretic effect but later there is direct action on blood vessels

250
Q

Give 5 potential problems with thiazide diuretics

A

same as furosemide -hypokalaemia
metabolic alkalosis
decreased uric acid excretion

increase Mg2+ excretion but decrease Ca2+ excretion

251
Q

What is the average fall in plasma K+ when Thiazide diuretics are administered

When would this be a big problem

A

0.7mM

if thiazides were combined with cardiac glycosides, as lower [K+]plasma can potentiate action of cardiac glycosides

252
Q

Which diuretics do not have the side effect of K+ loss

A

Potassium-sparing diuretics

diuretics that don’t have the K+ loss of loop diuretics and thiazides

253
Q

What are the 3 main potassium sparing diuretics?

What is the mechanism of their action

A

amiloride
triamterene
spironolactone

they have different ones but each depend on the fact that in the late DCT Na+ enters cells down a conc gradient generated by the Na+/K+ ATPase K+ and H+ are drawn into the lumen by the potential gradient across the apical membrane (which in turn is created by Na+ movement). This is a major site of K+ loss into the urine.

254
Q

How do amiloride and triamterene work

What level is the diuretic effect

A

prevent Na+ reabsorption by blocking apical Na+ channels

weak but K+ loss is decreased

255
Q

How can we prove amiloride only acts on one side

A

amiloride only blocks Na+ transport when applied on the apical side

256
Q

How does spironolactone work

A

antagonist of aldosterone action by competing for binding on the aldo receptor in the cytoplasm

257
Q

How does aldo initiate a response

A

migrates across PM and combines with cytoplasmic receptor

the whole complex is translocated to the nucleus where it leads to synthesis of Na+/K+ ATPase and ENaC

258
Q

How can the action of aldo be proved

A

an aldosterone-induced increased in C14-amiloride binding

259
Q

What is spironolactone metabolised into and where does it occur

A

into canrenone in the liver

260
Q

True or false

The effects of spironolactone are thought to be due to its metabolism

A

True

K+-canrenone works as a K+ sparing diuretic

261
Q

When is the effect of spironolactone significant

A

only when the DCT is under influence of aldo

262
Q

What are potassium sparing diuretics often used in conjunction with

A

thiazides or loop diuretics to counteract hypokalaemia

263
Q

How fast is the rate of onset for diuresis after spironolactone is administered

A

slow as mechanism depends on turnover of Na+ channels

264
Q

Are Na+ channels in epithelial cells the same as in nerves?

Why is this important

A

NO - they are no voltage gated and have different structure

different susceptibility to drugs

265
Q

What is the major drug in the carbonic anhydrase inhibitor diuretic

A

acetazolamide

266
Q

What were the first diuretics to be introduced

What is the aim of them

A

CA inhibitors

To inhibit NaHCO3 reabsorption in the PCT and DCT by decreasing amount of H+ available

267
Q

Where is CA located inthe kidney

A

brush border of PCT and intracellularly

only intracellularly in the DCT

268
Q

What is the net NaHCO3 reabsorption driven by

A

Na/K pump

269
Q

How is urine pH affected by CA inhibitors

A

pH increases as HCO3- content increases

270
Q

How effective are CA inhibitors as diuretics

A

v weak diuretics

mainly used to treat glaucoma

271
Q

How are CA inhibitors used to treat glaucoma

A

suppress HCO3- secretion, preventing formation of aqueous humour in the eye

272
Q

How can the action of CA inhibitors be controlled

A

self limiting because excess HCO3- loss leads to metabolic acidosis

273
Q

What can acetazolamide be used for other than as a diuretic

A

acclimatization to high altitudes

alleviate sleep apnoea at altitude

274
Q

Which type of diuretic has the simplest function

A

osmotic diuretics eg mannitol

275
Q

How do osmotic diuretics work

A

small Mr filtered at glomerulus but not reabsorbed
Draw in water, increasing urine volume level
Also decrease Na+ reabsorption by decreasing [Na+]

276
Q

When are osmotic diuretics usful

A

where urine flow is reduced due to decreased GFR, leading of excessive salt and water reabsorption
Urine flow can cease in distal nephron, permanently damaging it
Osmotic diuretics increase flow

277
Q

What can mannitol be used for acutely

A

to rapidly reduce intracranial and intraocular pressure

useful in cerebral oedema

278
Q

How does mannitol cross the BBB

A

it cannot

279
Q

How can diuretics affect blood pressure

A

reduce blood pressure

280
Q

What are the 3 key hormones of blood pressure control

A

ATII
aldosterone
ANP

281
Q

A rise in what second messenger leads to renin release

A

cAMP

282
Q

Name 3 things which reduce renin release

A

adenosine (acting on A1 receptors which inhibit cAMP formation)

ANP (via cGMP)

negative feedback by ATII (IP3 mediated response)

283
Q

Where is angiotensinogen produced

A

it is a plasma globulin manufactured in the liver

284
Q

Describe ACE

A

membrane-bound carboxypeptidase and is

most abundant on the endothelium and smooth muscle of the lung

285
Q

true or false

ACE is only found in the lungs

A

false

also found in kidney and other organs

286
Q

What is kininase II

A

AKA Angiotensin converting enzyme

breaks down bradykinin

287
Q

How is antagonism of the renin angiotensin system mainly achieved

Give 3 examples

A

ACE inhibitors

ramipril
lisinopril
perindopril

288
Q

What is saralasin?

A

ATII partial agnoist

289
Q

What is the issue with saralasin

A

it is a peptide so is not suitable orally hence is not competitive with other hypertensive drugs

290
Q

Have we developed any non peptide ATII antagonists

A

yes eg losartan

291
Q

what does losartan act on

A

AT1 receptor (a receptor for angiotensin II - DO NOT CONFUSE WITH ANGIOTENSIN I)

292
Q

What is the role of AT2 receptors

A

activation leads to vasodilation by NO production and cGMP increase

binding of angiotensin II to teh AT2 receptor inhibits cell proliferation, mediates differentiation in neural tissue and can induce apoptosis

293
Q

What kind of heart failure should ACE inhibitors be useful for theoretically

A

when associated with high renin levels

294
Q

Why are ACE inhibitors beneficial in heart failure

A

useful in ,old heaty faikure becaise the failing heart activates renin so ACE inhibitors can reducce pre- and aferload

reduce TPR not BP

295
Q

How can ACE inhibitors decrease TPR but not BP

A

heart can compensate by Increasing CO

296
Q

Which drugs are ACE inhibitors often combined with

Why can this be useful

A

diuretics

reduced aldo should help avoid hypokalaemia

297
Q

Which end does ACE cleave to form ATII

How can ATIII and ATIV be formed

A

C terminal

successive cleavage of the N terminal end

298
Q

What do ATIII and ATIV do

A

Have same affinity for AT1 and 2

intracerevroventricular injection of either increases ADH release and increases BP

299
Q

Can ATII be converted into ATIII

What are the clinical implications of this

A

yes by brain aminopeptidase-A

aminopeptidase A could be used as a central theerpeutic target for hypertension

300
Q

Where does ATIV act primarily

A

brain - innvoled in learning, memory and long term potentiation

301
Q

Which enzyme produces AT IV

A

aminopeptidase-N

302
Q

Which receptor may be activated by AT IV

A

AT4

303
Q

How are AT4 receptors different from AT1 and 2

A

they are

transmembrane-located enzymes called insulin-regulated membrane aminopeptidase (IRAP).

304
Q

Are AT4 receptors widely distributed?

A

Yes - not just in the brain

305
Q

Clinical application of AT4 receptors

A

memory enhancement, eg in Alzheimer’s disease

306
Q

True or false

Hypotension is dangerous with any ACE inhibitor

A

true - risk of renal failure is increased by the blockade of efferent arteriole constriction (mediated by ATII)

307
Q

Describe bradykinin

A

short peptide
potent natriuretic
renal vasodilator

308
Q

Where in the kidney can kininogen and kallikrein be found

A

early DCT

collecting duct is also rich in kininogen as well as B2 bradykinin receptors

309
Q

Where is bradykinin metabolised in the kidney

A

PCT which is rich peptidases which can metabolise it

310
Q

What is the role of the kallikrein-kinin system in the kidney

A

minimal noramlly

but if high Na+ reaches the DCT, kallikrein is released and bradykinin is formed from kininogen, inhibiting Na+ reabsorption

311
Q

How does ANP act

A 
via a membrane-bound
guanylate cyclase (GC-A) receptor to form cGMP with the aim of reducing BP and blood volume
312
Q

True or false

ANP is a directly acting vasodilator

A

true but does also reduce NA release

313
Q

How does ANP promote diuresis

Where is its main effect

A

increasing GFR
decreasing Na+ reabsorption

collecting duct

314
Q

How does ANP effect renin

A

decreases it release

315
Q

Which drugs affect ANP

A

There are no useful drugs acting to influence ANP (or its receptors)

316
Q

Are defects in the ANP system involved in hypertension

A

not really

however, mice lacking the GC-A gene are hypertensive (which is not made worse by a high-salt diet).

317
Q

Hypertension is rarely caused by a single cause. Give one exception of a cause of hypertension and what it is

A

One exception to this is phaeochromocytoma (an adrenaline-secreting tumour of chromaffin cells in the adrenal medulla)

318
Q

how common and dangerous is phaeochromocytoma

A

not common but when it does occur it is very dangerous

319
Q

what is it called when the majority of renal artery disease have no obvious single cause

A

essential hypertension

(this comes from the fact that it was once thought to be essential to
have high blood pressure to maintain tissue perfusion)

320
Q

what is the approx diastolic and systolic pressure of a young adult, and give the mean arterial pressure

A

distolic pressure- 80mm Hg

systolic pressure - 120mm Hg

mean arterial pressure - around 96mm Hg

321
Q

what is the broad pressure in mild hypertension for diastolic and systolic

A

diastolic pressure is > 90 mm Hg, systolic > 140 mm Hg

322
Q

give the 6 mechanisms that are most significant involved in development of essential hypertension

A 
Cardiac output
• Peripheral resistance
• The renin-angiotensin-aldosterone system and the kidney
• The autonomic nervous system
• The endothelium
• Vasoactive peptides
323
Q

what must be reduced to reduce blood pressure

A

CO or TPR

324
Q

what causes TPR?

A

arteriolar resistance

325
Q

what changes does chronic smooth muscle contraction lead to?

A

thickening of the arteriolar vessel walls - possibly mediated by angiotensin - leading to an
irreversible rise in peripheral resistance.

326
Q

What has been proposed about resistance in early hypertension

A

the
peripheral resistance is not raised and the elevation of the blood pressure is caused by a raised
cardiac output, which is related to sympathetic overactivity

327
Q

If in early hypertension, the
peripheral resistance is not raised and the elevation of the blood pressure is caused by a raised
cardiac output, which is related to sympathetic overactivity, what is the subsequent rise in TPR due to

A

develops in a compensatory manner to prevent the raised

pressure being transmitted to the capillary bed where it would affect cell homeostasis

328
Q

Do NA and adrenaline have a role in essential hypertension

A

there is little evidence to support this

329
Q

If there is little evidence for role of NA and adrenaline in the etiology of essential hypertension, are SNS blockers still useful?

A

yes they do lower blood pressure

330
Q

name 2 vasoactive agents produced by the endothelium

Why is this important clinically

A

NO
endothelin

Dysfunction of the
endothelium has been implicated in human essential hypertension

331
Q

What happens to NO in atheroma

A

endothelial NO production is compromised

332
Q

Describe some of the effects of endothelin (3)

A

vasoconstrictor
may produce a salt sensitive rise in BP
activate renin - angiotensin systems

333
Q

What suggests that endothelial dysfunction becomes irreversible once the
hypertensive process has become established.

A

Some antihypertensive therapy seems to restore impaired production
of nitric oxide, but paradoxically does not necessarily restore the impaired endothelium-dependent
relaxation.

334
Q

Is the circulating renin angiotensin system thought to be responsible for the rise in BP in hypertension?

A

not directly

hypertensive patients tend to have low levels of renin and angiotensin II

335
Q

Name 2 vasoactive peptides

A

ANP

Bradykinin

336
Q

What inhibits bradykinin

A

ACE

337
Q

Apart from any effect on angiotensin, why might ACE blockers lower BP

A

ACE inhibits bradykinin so ACE inhibitors block bradykinin’s inactivation

338
Q

If circulating renin-AT systems aren’t important in hypertension, why is understanding of renin and AT still important?

A

local renin-AT paracrine systems also control BP

339
Q

Where have local renin AT systems been reported

What are these systems important for?

A

in the kidney, the heart, and the arteries

regulating regional blood flow

340
Q

How many genes have been found to cause hypertension and hypotension

A

hypertension: 8
hypotension: 9

341
Q

Name an inherited hypertensive mutation

A

Liddle’s syndrome

342
Q

Describe Liddle’s syndrome

what is it, what is the mutation, what is the result

A

inherited hypertensive syndrome

mutation in beta and gamma subunits of ENaC in DCT - channels are both over expressed and open more frequently

high rate of Na reabsorption in presence of low aldo secretion

343
Q

What is a paracrine hormone

A

a hormone whose effects are confined to tissues in the vicinity of the gland secreting it

344
Q

What is striking about the mutated gene products that have been shown to definitely be associated with hypertension

A

they all act on the kidney, altering net renal salt reabsorption

345
Q

Give 3 pieces of evidence suggesting the key role of the kidney in the aetiology of essential hypertension

A

all gene mutations which definitely cause hypertension affect the kidney

cross transplantation of kidneys from hypertensive rats to non-hypertensive rats

human evidence from renal transplant recipients shows
that they are more likely to develop hypertension if the donors’ relatives are hypertensive

346
Q

Name 7 antihypertensive drug types

A

Diuretics

ACE inhibitors

beta blockers

alpha 1 AR blockers

Ca channel blockers

K channel openers

Centrally-acting alpha2/I1 -agonists

347
Q

What are the 2 phases of the effects of diuretics on hypertension

A

initially: decrease blood volume
latter: vasodilation

348
Q

How long does it take for full hypotensive effect to take place when taking diuretics

A

up to 12 weeks

349
Q

What is a common side effect of ACE inhibitors

A

(possibly severe) dry cough

350
Q

When is it logical to use ACE inhibitors in hypertension

A

when plasma renin is high

351
Q

How many hyper tensive patients respond to ACE inhibitors

A

50-75% mild-moderate

hypertensives respond to ACE inhibitors

352
Q

What is useful to combine with ACE inhibitors to reduce hypertension

A

diuretics

353
Q

What is used to treat patients who are intolerant to ACE inhibitors

A

ARBs

354
Q

Have beta blockers been used successfully to treat hypertension?

A

yes very much so

355
Q

What kind of beta blockers are preferable to treat hypertension?

A

beta 1 specific are preferred over non- specific (non-specific can result in bronchoconstriction)

356
Q

Name 2 b1 specific beta blockers

A

atenolol and bisoprolol

357
Q

What is likely the cause of the effectiveness of b1 blockers in hypertension

A

Decreased cardiac output (as a result of ßl
blockade).
• Decreased plasma renin
• CNS action

358
Q

How well does atenolol penetrate the CNS

How does this impact its effect on hypertension

A

not much as it is hydrophilic

it decreases blood pressure just as effectively as penetrant antagonists

359
Q

Are beta blockers still the mainstay of hypertensive treatment?

A

They are now being eclipsed by other drugs, primarily because many patients
suffer significant unwanted effects with ß-blockers, especially in the CNS (e.g. insomnia and
depression).

360
Q

Give 2 of the CNS side effects of beta blockers

A

insomnia

depression

361
Q

Are a1 ARBs used for hypertension

A

yes but are not frontline drugs

362
Q

What is the best known example of a1 ARBs used to treat hypertension amongst veteran
pharmacologists

A

prazosin

363
Q

What is the most used modern a1 blocker

A

doxazosin

364
Q

How is the tone of arterioles usually controlled

A

via a1 AR sympathetic control causing vasoconstrictio

365
Q

What might cause a non selective a1 blockade

What does this give

A

phentolamine

vasodilatation and
as a result a marked reflex tachycardia.

366
Q

How does increased SNS activity affect renin

A

increases renin secretion

367
Q

What does doxazosin do in hypertension

A

a1 AR blocker

dilates resistance and capacitance vessels
no marked tachycardia

368
Q

why is there no marked tachycardia from doxazosin

A

lack of block of presynaptic á2

-receptors.

369
Q

What decreases SNS activity when doxazosin is administered

A

Blockade of CNS á1
- receptors modulates baroreceptor
reflex mechanisms

370
Q

What is labetalol?

A

an unusual drug being an á1
, ß1
and ß2
antagonist (But more so ß than á).

371
Q

What do Ca channel blockers act on

A

on L-type Ca2+

channels

372
Q

What effects do Ca channel blockers have other than their cardiovascular effect

A

mild diuretic effect, independent of any change in renal

blood flow or GFR

373
Q

What causes the mild diuretic effect caused by Ca channel blockers

A

Ca2+
channel blockade may inhibit aldosterone release which is
stimulated by angiotensin II

374
Q

How do Ca channel blockers affect baroreflexes

A

antagonise baroreceptor

reflexes, but this is most probably not important in long-term control.

375
Q

what was the original dihydropyridine drug?

Is it still used?

A

nifedipine

yes but amlodipine is more commonly used

376
Q

What is the most commonly used Ca channel blocker?

A

amlodipine

377
Q

what is the only K channel opener in general use for hypertension

What is an example that is used in angina

A

minoxidil

nicorandil

378
Q

Describe the action of K channel openers

A

They act on ATP-sensitive K+
channels in vascular smooth muscle, resulting in
hyperpolarisation and relaxation. Normally, intracellular ATP closes the channel, leading to
depolarisation and contraction. The same mechanism causes insulin release from pancreatic
ß cells.

In non-pancreatic cells this is suggested to be a protective mechanism

KCOs antagonise action the
action of ATP.

379
Q

What opposes depolarisation of ischemic cardiomyocytes

A

the fall in ATP opens the channels, opposing depolarisation.

380
Q

What is a KCO used in severe refractory hypertension and what is it used with

A

Minoxidil with a ß-blocker and diuretic to

counteract respectively reflex tachycardia and any increase in blood volume

381
Q

What is a side effect of minoxidil

A

hirsutism

382
Q

Which KCO can be used aesthetically?

A

minoxidil - has some use as a topical hair loss treatment

383
Q

What does minoxidil work best on topically

How well does it work

How is it found now?

A

early male pattern baldness, but even then it is not spectacularly successful.
Even less so on totally bald heads.

It is sold as a shampoo containing 2% minoxidil

384
Q

What are the archetypal centrally acting a2/i2 agonists

A

clonidine

guanfacine

385
Q

How was clonidine originally thought to act

A

by decreasing noradrenaline release via an
action on presynaptic á2
receptors in the CNS.

386
Q

How can you administer clonidine to decrease bp

A

microinjection into ventrolateral medulla (brainstem)

387
Q

Why is it effectobe to microinject clonidine into the ventrolateral medulla of the brainstem?

A

This is an area rich in á2
receptors, but in fact the effect may be mediated by a new
class of receptor, the imidazoline I1
receptor

388
Q

What usually acts on I1 receptors

What is this mimicked by?

A

catecholamines

imidazoline drugs (such as moxonidine)

389
Q

Which is a more potent a2 agonist: clonidine or guanfacine ?

A

guanfacine - BUT has low efficacy as an antihypertensive

390
Q

How does moxonidine act on hypertension

A

as a centrally acting antihypertensive but
has fewer side-effects than á2
agonists.

391
Q

Generally, what is involved in the I1 receptor pathway?

A

G-protein coupling to specific transmembrane signalling

pathways, leading to the generation of diacylglycerol and arachidonic acid.

392
Q

Name a false transmitter used to treat hypertension

A

á-methylnoradrenaline

taken as á-methyldopa to be converted to á-methylnoradrenaline in vesicles of adrenergic neurons

393
Q

How well does á-methylnoradrenaline act on different ARs?

A

less potent than noradrenaline on á1
receptors, but more potent on á2
.

394
Q

What is a problem with centrally acting antihypertensive drugs

A

Sudden withdrawal leads to rebound but this is

much less marked after withdrawal of moxonidine than after withdrawal of clonidine.

395
Q

Which blood vessels does atherosclerosis affect

What is atherosclerosis colloquially described as

A

arterial

arterial ‘hardening’

396
Q

What is an atheroma

A

is the accumulation of a
soft, flaky, yellowish material at the centre of large plaques, composed of macrophages nearest the
lumen of the artery. The process is progressive and the effects cumulative.

397
Q

What is the etymology of atheroma

A

a (“lump of porridge” from “athera” - porridge in Greek)

398
Q

How can atheromas change to more complex lesions

A

with underlying areas of cholesterol crystals, and also calcification
in more advanced stages

399
Q

How can an atheroma lead to angina

What are 2 other scary outcomes of atheroma

A

atheroma leads to stenosis and compromises the arterial supply, and can produce
myocardial ischaemia, leading to angina

parts of the atheromatous tissue can break
off, or can form a good substrate for clot formation. The result of either of these events may be
complete occlusion of part of the coronary circulation with resulting myocardial infarction

400
Q

What does chronic under perfusion of the myocardium lead to

What if it affects conductive tissue

A

congestive heart failure

dysrhythmia

401
Q

What is the difference between arteriosclerosis and atherosclerosis

A

The term
‘arteriolosclerosis’ generally, though not exclusively, refers to changes seen at arterioles, while ‘atherosclerosis’ is due
specifically to an atheromatous plaque. Therefore, atherosclerosis is a form of arteriosclerosis

402
Q

How does atherosclerosis affect the legs

A

claudication from insufficient blood supply to the legs in advanced disease

similar events can occur in other organs due to atheromas

403
Q

What is an effectvie way to reduce incidence of serious events arising from atherosclerosis

What is the most common therapy to do this

A

reducing plasms lipids

to reduce blood cholesterol either through dietary changes or drugs

404
Q

How is cholesterol transported in the blood

How does this relate to risk of atheroma

A

in lipoproteins

excessive low-density lipoproteins (LDL) especially predispose to atheroma

405
Q

What are lipoproteins composed of

A

cholesterol intercalated in a phospholipid membrane and
cholesteryl esters.

apolipoproteins are associated with the lipid particle (different lipoproteins have different apolipoproteins)

406
Q

What are the different apolipoproteins in

a) LDL
b) HDL

A

a) ApoB

b) mainly ApoA

407
Q

True or false
LDL seems to protect against atheroma development

Therefore how can you sum up the goal of atheroma drug therapy simplistically?

A

FALSE
In
contrast to LDL, HDL seem to be protective against atheroma development

decrease LDL and increase HDL (if possible)

408
Q

How does LDL enter the hepatocyte

A

receptor mediated endocytosis

409
Q

What does the bile produced by the liver contain

where is it secreted into

what happens to it

what does this mean

A

contains cholesterol and bile salts

duodenum

much of it is reabsorbed,
together with emulsified fats from later sections of the GI tract

there is a
circulating pool of bile salts and cholesterol ( the enterohepatic circulation).

410
Q

How is the enterohepatic circulation topped up

A

with newly synthesised cholesterol, or cholesterol that has been taken up by the liver, the source
being LDL.

411
Q

Name 2 statins

A

atorvastatin

simvastatin

412
Q

What do statins do

How is this useful

A

inhibit HMG-CoA reductase

increases circulating LDL uptake by the liver so blood LDL levels drop, and risk of atheroma formation drops

413
Q

What enzyme is responisble for the rate limiting step in cholesterol synthesis

A

HMG-CoA reductase

hydroxymethylglutaryl-coenzyme A reductase

414
Q

What happens in HMG-CoA is blocked

A

liver has to take up more LDL from the blood (to keep the

cholesterol pool for the enterohepatic circulation topped-up)

415
Q

How does the liver take up more LDL from the blood when statins are taken

A

synthesising new LDL receptors

416
Q

Who are statins prescribed for currently

A

people who either already have

ischaemic heart disease, or who are in ‘high risk’ groups (normally based on family history)

417
Q

What is SRE

Where is it found

What is its job?

A

sterol response element

in the LDL receptor gene promoter

monitors presence of sterols in the cell and reguates LDLD receptor transcription

418
Q

Does the SRE up or down regulate LDL receptor expression

A

up OR down according to cellular sterol levels

419
Q

What are the 2 key molecules that interact with SRE

A

SRE-binding proteins 1 and 2 (SREBP-1 and -2).

420
Q

Describe the structure and normal location of SREBPs

A

contain two transmembrane domains

and are normally anchored in the ER

421
Q

How are the SREBPs taken to the Golgi from the ER

A 
SREBP cleavage
activating protein (SCAP) acts as a chaperone protein and it transports the precursor SREBPs  to the Golgi.
422
Q

What happens to the SREBPs in the Golgi

What is important to remember about this reaction

A

two proteases, site 1 and site 2 protease (S1P
and S2P) sequentially cleave the SREBPs

These cleavages must occur in the proper order and the
first cleavage, by S1P, separates the SREBPs into two halves, both of which remain membrane bound

423
Q

What happens after the 2 halves of SREBP have separated

A

S2P cleaves the remaining NH2
-terminal
fragment, liberating the mature SREBPs from the membrane

SREBPs now enter the nucleus and bind SRE to activate LDL receptor gene transcription

424
Q

How does the overall benefit of statins compare to what it should be theoretically

What does this suggest

A

benefits are greater than that which might be expected
from changes in lipid levels alone.

effects independent of cholesterol-lowering
might occur

425
Q

What are other benefits of the pleiotropic effects of statins (5)

A

improvement of endothelial function,

enhancement of the stability of atherosclerotic plaques,

a decrease in oxidative stress and inflammation,

inhibition of thrombus formation

beneficial extrahepatic effects on the immune system, CNS and bone

426
Q

How do the brains of people who took statins differ from those who did not

A

The statin-treated group showed

significantly fewer pathological features of Alzheimer’s disease

427
Q

Why do we want alternatives to statins

A

Statins have been very successful, but come with some disadvantages.
eg in some individuals intolerance and adverse effects

less effective in
some in lowering of cholesterol levels.

428
Q

What are recently introduced drugs that are statin alternatives

A

PCSK9 Inhibitors

429
Q

What is PCSK9

A

(proprotein convertase subtilisin/kexin type 9 - is a circulating enzyme, produced by the liver, that is involved in LDL receptor turnover.

430
Q

What happens when PCSK9 interacts with the LDL receptor

A

stimulates receptor internalisation and
degradation

hence leads to fewer receptors at the PM to bind and allow the cell to take up LDL-cholesterol

431
Q

What are Evolocumab and alirocumab

What do they lead to

how must they be administered

A

monoclonal antibodies, that target and inhibit PCSK9

enhance the internalisation and recycling of LDL receptors (and hence uptake of LDL)

injection

432
Q

Name 2 PCSK9 inhibitors

A

Evolocumab

alirocumab

433
Q

Name a fibric acid derivative which lowers VLDL and LDL

A

bezafibrate

434
Q

What does bezafibrate do

How does this help

What molecule does the action action rely upon

A

stimulates lipoprotein lipase, releasing triglycerides from VLDL and chylomicrons

lipid can then be taken up and stored in fat or metabolised in skeletal muscle

hinges upon mechanisms of HDL processing

435
Q

How does HDL provide protection from ischaemic vascular disease

A

reverse cholesterol transport

removal of cholesterol from peripheral tissue tp the liver for excretion in bile. It is transported from the tissue to the liver in HDL

436
Q

How is cholestrol transferred to the HDL from non-hepatic tissue

What is it transferred to in the first step of the mechanism

A

by the ATP-binding cassette transporter ABCA1

simply to ApoA-1 as
a first stage in building-up the lipoprotein

437
Q

What does Apo-A act as in reverse cholesterol transport

What is the role of the rest of the HDL molecule

A

acts as an acceptor

the phospholipid component of HDL acts as a sink for the mobilised
cholesterol.

438
Q

What happens to the cholesterol to prepare it for transport in the HDL

A

converted to cholesteryl esters by the

action of the enzyme lecithin cholesterol acyltransferase (LCAT).

439
Q

What can cholesteryl esters be transferred to

However, what mediates most of the liver’s uptake of cholesteryl esters from HDL

A

other lipoproteins (including LDL) that can be taken up by the liver by the LDL receptor

the receptor SR-B1 (‘Scavenger Receptor B1)

440
Q

What is SR-B1

Where is it found and what can it do

A

Scavenger Receptor B1

present on liver cells’ PMs

mediates most of the liver’s uptake of cholesteryl esters from HDL

441
Q

What happens when the cholesteryl esters from HDL in the liver

A

converted to cholesterol and enter the general pool.

442
Q

What is the rate limiting step of HDL formation

A

removal of cellular phospholipids and cholesterol by apoproteins or by lipid-poor HDL from peripheral cells and tissues.

443
Q

What is Tangier disease

A

A very rare, inherited disease that is found in some inhabitants of Tangier Island in Chesapeake Bay in the USA.

sufferers have vvv low HDL levels

444
Q

What did a study of people with Tangier disease show

A

that ABCA1 controls the rate-limiting step in cellular phospholipid and cholesterol efflux.

445
Q

How is expression of ABCA1 controlled

A

d by the cell’s content of cholesterol via activation

of ‘liver X receptors’ (LXRs

446
Q

What do LXRs act as

A

metabolic sensors for cholesterol content of cells, allowing

the organism to quickly adapt to increases in cholesterol levels.

447
Q

What induces LXR transcription in cells

what does this lead to

A

The nuclear receptors, peroxisome
proliferator-activated receptor (PPAR)alpha and PPARgamma

increased LXR alpha transcription induces ABCA1 expression

448
Q

Name a PPAR gamma agonist

A

pioglitazone

449
Q

What is pioglitazone used to treat

A

T2 diabetes

also reported to reduce atherosclerosis

450
Q

How do fibrate drugs work overall

A

activating PPARs

451
Q

Name 2 agents that are involved in enterohepatic circulation (not fibrate drugs)

A

Colestyramine

Ezetimibe

452
Q

What is colestyramine

what does it do

A

an anion exchange resin

prevents reuptake of bile acids from the
intestine. This causes an increase in cholesterol metabolism to synthesise bile acids in the liver.

453
Q

What does ezetimibe do

Is it usually used alone?

A

inhibits the intestinal absorption of cholesterol.

can be used in combination with a statin or alone

454
Q

What is the molecular target of ezetimibe

A

‘Niemann-Pick C1-Like 1’ (NPC1L1)

455
Q

What is ‘Niemann-Pick C1-Like 1’ (NPC1L1) named after

this is just a foot note so not as important

A

Niemann-Pick disease, (three types, A, B and C)

genetic, ultimately fatal lipid storage conditions that lead to abnormal accumulation of sphingolipids in the brain, liver spleen and bones. Mutations in NPC1 and NPC2 lead to type C of the disease. Niemann-Pick disease is rare, (not as rare as Tangier disease)

456
Q

What does NPC1L1 do

A

mediates sterol transport across the brush border of intestinal epithelial cells and is also present in
the liver where it helps in the reabsorption of cholesterol from bile

457
Q

Why can ezetimibe be reused by the body over and over again

A

it circulates enterohepatically (between the intestine and the liver), meaning that it is repeatedly redelivered to the intestine, where it can exert its action all over again.

458
Q

How does nicotinic acid affect blood LDL (3)

A

inhibits liver triglyceride production and VLDL secretion when used in very large doses.
It increases levels of t-PA

459
Q

What are the effects of fish oil

A

reduces hypertriglyceridaemia by an unknown mechanism

reduces
pancreatitis due to hypertriglyceridaemia.

The increased amounts of highly unsaturated fatty acids in fish oil reduces risk of thrombosis.

460
Q

How does the increased amounts of highly unsaturated fatty acids
in fish oil reduces risk of thrombosis

A

e eicosapentaenoic acid they contain substitutes for arachidonic acid in production of prostaglandins and thromboxanes.

Eicosapentaenoic acid produces PGI3
instead of PGI2
in endothelial cells, without a great change in antithrombotic activity but the TXA3
produced in platelets is much less effective than TXA2
at causing platelet aggregation.

461
Q

What is the etymology of angina

A

gina
The term ‘angina pectoris’ comes from the two Latin words angere and pectus (meaning
strangle and chest respectively).

462
Q

What is angina

A

severe, suffocating chest pain

463
Q

Where can angina pain be referred to

A

left shoulder and upper arm and sometimes the teeth

464
Q

What is variant angina

What provokes it

How does it compare to regular angina

A

‘Prinzmetal’s’ angina’.

coronary
arteries go into spasm spontaneously, producing angina without the necessity for coronary arteries to be blocked with atheromatous plaques.

No obvious stimulus provokes an attack of variant angina.

Although it is reputedly even more painful and debilitating than classical angina pectoris.

465
Q

why is the coronary circulation unusual

A

during
systole, the myocardium receives little blood (and so oxygen) supply, but blood does perfuse the
myocardium during diastole

466
Q

Why is the myocardium only supplied with blood during diastole

A

in systole, the myocardium is contracted.

This means that
lateral pressure is applied onto the sub-endocardial vessels of the coronary circulation which supply most of the oxygen to the myocardium.

467
Q

What kind of innervation tends to predispose angina patients with pain

Why (3)

A

SNS

  1. Increases heart rate, reducing the proportion of the time the heart is in diastole and thus capable of being perfused.
  2. Increases force of contraction (and thus oxygen demand).
  3. Deceases cardiac efficiency (more oxygen used to perform the same mount of work).
468
Q

Why is SNS stimulation on the heart not a problem for non-angina patients

A

SNS usually causes dilation of coronary vessels which increases coronary blood flow

In ischaemic heart disease/ angina, atheroma means the vessel needs to be fully dilated at rest to perfuse the myocardium. thus the coronary vessels cannot increase any further when demand increases

469
Q

How do angina patients’ bodies compensate for the decreased blood flow

A

angiogenesis: they develop collateral blood vessels

470
Q

Who is sudden death occlusion of coronary arteries more likely to be fatal in:
a) a younger patient
or
b) one who has had angina for an extended period

A

b

they have had time to adapt to the ischaemia so have had more angiogenesis
The longer a person suffers ischaemic
heart disease, the more time the myocardium has to develop collateral vessels

471
Q

Can a normal person develop collateral blood vessels?

A

yes, develop in normal individuals who take regular, sustained aerobic exercise.

472
Q

Why is the term nitrovasodilators a misnomer

A

all of these drugs are in fact organic

nitro derivatives

473
Q

Name 3 nitrovasodilators

When are each used?

A

glyceryl trinitrate

isosorbide mononitrate

amyl nitrite

first 2 in angina (glyceryl trinitrate especially in acute attacks)
amyl nitrate is a recreational drug (Poppers)

474
Q

How is glyceryl trinitrate taken

why

A

sublingually

s poorly absorbed from the stomach
and so it is taken sublingually (where it is absorbed directly into the systemic circulation)

475
Q

What is required to happen to isosorbide dinitrate for it to work

A

metabolised in the liver to isosorbide mononitrate

476
Q

How do nitrovasodilators cause vasodilation

A

by being converted to
nitric oxide (NO) in vascular smooth muscle cells by endothelial cell Ca2+
-sensitive nitric oxide synthase - ecNOS

477
Q

What is glyceryl trinitrate also used in

A

This is actually nitroglycerin, the major component of dynamite

478
Q

What is the main way nitrovasodilators work in angina patients

A

venous dilation

can also cause collateral vasodilation
remember coronary arteries cannot dilate more

479
Q

Why does nitrovasodilators causing venous dilation help with angina

A

reduced central venous pressure, the right atrial filling pressure and
thus the work done by the heart (Starling’s Law)

480
Q

what is the fortuitous feature of the action of nitrovasodilators

A

they produce vasodilatation in collateral vessels in ischaemic areas, while not affecting dilatation in well oxygenated areas

481
Q

What is coronary steal

A

when vasodilator drugs, such as dipyridamole (which stimulates adenosine receptors) open all vessels (not only in ischaemic, but also in well oxygenated tissues) and diverts
the blood away from the ischaemic region.

482
Q

What drug causes coronary steak

A

vasodilator drugs, such as dipyridamole (which stimulates adenosine
receptors)

483
Q

What can be a secondary response to use of nitrates to alleviate angina?

A

A severe headache

Changes in cerebral blood flow can cause severe headaches. This partly explains what happens in migraine.

484
Q

Name 2 ß1

antagonist

A

bisoprolol and atenolol

485
Q

How are ß1

antagonist useful in angina

A

decrease SNS stimulation on heart

decrease blood pressure to decrease afterload (reducing work done by the heart)

486
Q

why are non specific beta antagonists less useful in angina

A 
unwanted effects:
eg bronchoconstriction 
coronary vasoconstriction (alpha 1 mediated)
487
Q

Why do non specific beta blockers result in coronary vasoconstriction

A

Coronary blood vessels also have ß2 receptors (which normally cause vasodilatation) and also alpha1
receptors that
produce vasoconstriction. Normally the alpha response is overwhelmed by the ß2
response, but nonspecific ß-antagonists inhibit this, and unmask the alpha1
-mediated constriction

488
Q

Why might it be dangerous to completely block the SNS with beta blockers in an angina patient

A

In heart failure (which
frequently occurs concurrently with angina) it is necessary to maintain sympathetic stimulation to
produce an adequate cardiac output

489
Q

How do dihydropyridine channel blockers act

A

t by blocking Ca2+
entry into vascular smooth
muscle cells, causing vasodilation, reduced BP and reduced afterload

490
Q

What is the most commonly used dihydropyridines Ca2+ channel antagonists

A

amlodipine

491
Q

why do dihydropyridines work on
vascular smooth muscle in preference to cardiac Ca
2+ channels?

A

vascular smooth muscle has a lower resting potential (-50 to -60mV) than cardiac (-80 to -90mV)

Thus more channels remain inactivated in smooth muscle than cardiac

dihydropyridines
bind to the inactivated form of the channel

492
Q

Name a If blocker

Which protein does it actually block

A

ivabradine

HCN channel

493
Q

Where is the If current highly expressed in the heart

What is the effect of blocking it

A

SAN

reduces cardiac pacemaker activity, slows the heart rate and allows more time for blood to
flow to the myocardium

494
Q

Why does ivabradine often help angina patients (other than allowing more time for blood to perfuse the myocardium)

A

people with stable angina often have very high heart rates, so ivabradine may help these individuals.

495
Q

Why does ivabradine not affect cardiac conduction, myocardial contractility or ventricular repolarisation.

A

acts on the HCN channel which is primarily in the SAN so the drug is selective to SAN

496
Q

What is a benefit of ivabradine over beta blockers in angina

A

ivabradine has few evident unwanted effects (unlike ß-adrenoceptor antagonists whose
use commonly results in respiratory side effects caused by constriction or spasm of the airways,
bradycardia or sexual dysfunction).

497
Q

Is ivabradine a popular drug?

A

No
patients usually have
to be inappropriate for, or have failed in some way on, a ß-blocker and/or dihydropyrodine
calcium channel blocker before it will be considered.

498
Q

What part of the heart does ivabradine act on

A

solely the SAN (not really AVN etc )

499
Q

What is the main mode of action of ranolazine

A

to inhibit the late phase of the sodium current in cardiac myocytes

(can act on other parts of the cardiac AP)

500
Q

What does the late Na current in the ischaemic myocardium AP result in

A

In the ischaemic myocardium, late inward Na+ currents result in a rise in [Na+]i, which in
turn leads to a rise in [Ca2+]i as a result of the influence of the higher [Na+]i
on the NCX

501
Q

What is the problem of Ca2+ overload in ischaemic cardiomyocytes following the late inward Na current

A

impairs relaxation, increasing ventricular diastolic wall stiffness and end-diastolic pressure, hence worsening ischaemia

502
Q

How does increased ventricular diastolic wall stiffness and end diastolic pressure result in increased ischaemia

A

stiffness causes mechanical
compression of the microcirculation within the wall of the ventricles, which impairs coronary blood
flow during diastole and worsens ischaemia

503
Q

How does ranolazine improve angina

A

Blocking late inward Na current means Ca2+ overload and diastolic wall
stress are reduced, leading to improved coronary blood flow and decreasing ischemia

504
Q

How is the degree of tissue damage following MI as a result of the initial ischaemic event determined

A

primarily determined by its duration, and then subsequent injury resulting from reperfusion.

505
Q

How can you improve the heart’s ability to withstand longer periods of ischaemia

A

ischaemic preconditioning

506
Q

What is ischaemic preconditioning

A

several short periods of ischaemia (e.g. three 5 minute occlusions of the bloodsupply separated by 5 minutes reperfusion) to increase the ability of the heart to withstand longer periods of ischaemia

provides the myocardium with the inherent ability to protect from ischaemic damage

507
Q

How can we use ischaemic preconditioning clinically

What is it used to treat

A

can be stimulated (it

seems) by use of the K(ATP)-opening drug, nicorandil, which can be used in angina

508
Q

What is the MPTP

A

mitochondrial permeability transition pore

s formed of a multimeric complex capable of forming large non-selective pores in the
otherwise highly impermeable inner mitochondrial membrane

509
Q

What does the MPTP do when the heart is reperfused after an ischaemic episode

A

opens (after remaining closed during the ischaemia)

510
Q

Name 4 things which can cause the MPTP to open

What is common about these 4 things

A

high mitochondrial [Ca2+], oxidative stress, ATP depletion and mitochondrial depolarisation,

all present during reperfusion.

511
Q

What does opening of the MPTP during reperfusion result in

What does this in turn lead to

A 
uncoupling of the respiratory chain, ultimately resulting in ATP depletion and generation of reactive
oxygen species (ROS)

leads to necrosis and in matrix swelling and subsequent rupture of then outer membrane, leading to release of pro-apoptotic proteins and ultimately apoptosis.

512
Q

What is responsible for the rise in mitochondrial ROS after ischaemia

A

accumulation of succinate (an intermediate of the citric acid
cycle) builds up during ischaemia

513
Q

What is the end effector of ischaemic preconditioning

A

A mitochondrial ATP-sensitive potassium channel (mitoK(ATP))

514
Q

How can opening of the mitoK (ATP) channel protect the myocardium after ischaemia

What provides evidence for this hypothesis

A

may slow rate of ATP depletion in ischaemia, increasing available energy to regulate ionic homeostasis, leading to better cell survival

nicorandil, a mitoK(ATP) channel opener, preserves ATP levels during ischaemia

515
Q

Why is energy state improved by opening of the mitoK(ATP) channel

A

decreases F1 Fo
-ATPase, which is the main consumer of ATP in ischaemia
(ATP synthase in reverse)

516
Q

Is the role of nicorandil solely as the mitoK(ATP) channel opener

A

no also is a nitric oxide donor

In addition nicorandil may open vascular plasma membrane KATP
channels, improving
perfusion, and the NO it produces may also enhance endothelium-dependent relaxation
mechanisms.

517
Q

How does nicorandil’s role as a nitric oxide donor help in preconditioning

A

s part of the phenomenon seems to be
mediated through a NO-dependent pathway (which is even less well understood that the MPTP
events).

518
Q

How can preconditioning be blocked and mimicked

A

by antagonists at adenosine receptors

can be mimicked by adenosine A1
receptor agonists

519
Q

How do interstitial [adenosine] change in ischaemia

What are the effects of this (3)

A

increase

adenosine has negative inotropic and chronotropic actions (to reduce cardiac oxygen demand).
also inhibits activation of neutrophils.

520
Q

What is revascularisation used to do

How can it be achieved

A

either to improve prognosis or symptoms

by either
coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).

521
Q

How was angioplasty achieved in the early 80s

What were the issues with this (2)
Give technical names of both

A

balloon dilation

re-narrowing of the vessel (‘restenosis’)
development of scar tissue that
encroached into the lumen (neointimal proliferation)

522
Q

What was the refinemetn made to the PCI technique introduced in the mid-1980s

How was this an improvement

A

use of intracoronary stents, small tubes made of a mesh of
metal.

prevented recoil and remodelling and nearly always resulted in a significantly better
dilatation than could be achieved with balloon dilatation alone

523
Q

What was the problem of stents in the late 1980s

How is this overcome

A

did not prevent neointimal proliferation (actually increased it)

‘drug-eluting stents’. They are coated
with a polymer within which are embedded antiproliferative drugs

524
Q

How common is restenosis in patients who have drug eluting stents

A

down to only 5-10% of cases

525
Q

WHat are the 2 types of antiproliferative drug eluting stents

A

The first elutes sirolimus

The second elutes
paclitaxel (also called ‘Taxol’) which interferes with the normal function of microtubule growth

526
Q

What is sirolimus commonly used as (other than in drug eluting stents)

A

as an immunosuppressant drug.

527
Q

What is Taxol used in other than in drug eluting stents

A

Paclitaxel/Taxol is used as an anticancer drug.

528
Q

How are antidysrhythmic agents classified

A

by the Vaughn Williams classification (I-IV)

529
Q

What are class I antidysrhythmic drugs

A

block Nav channels
subdivided into:
IA: increase AP duration with intermediate rate of association/ dissociation
IB: Decrease action potential duration, very fast association/ dissociation
IC: No effect on AP, very slow association and dissociation

530
Q

What are class IA antidysrhythmic drugs

2 examples

A

block VG Na channels
Increased action potential duration, with an intermediate rate of association/ dissociation.

quinidine and procainamide

531
Q

What are IB antidysrhythmic drugs

eg

A

block VG Na channels
Decreased action potential duration, with very fast association and dissociation. Example:
lidocaine

532
Q

What are IC drugs

eg

A

anti dysrhythmic drugs that block VG channels
No effect on action potential duration, but very slow association and dissociation.
Example: flecainide

533
Q

What are class II antidysrhythmics

A

Sympathetic antagonists (i.e. ß-blockers). Examples: propranolol, atenolol

534
Q

What are class III antidysrhythmics

A

these drugs prolong the action potential and thus also the refractory period. The best known
example is amiodarone

535
Q

What are class IV antidysrhythmics

A

These are Ca2+-channel blockers which reduce thus Ca2+ entry. The most commonly used is
verapamil

536
Q

What are class I antidysrhythmic agents useful for

A

block VG Na channels so V useful for suppression of
inappropriate APs in the types of cells that depend on the voltage-gated Na+
channels
to generate the action potentials

537
Q

Describe the affinity of Class IA antidysrhythmic drugs

what does this mean

What are they used to treat

A

affinity for the open (activated) state is greater than for inactivated. Thus, AP duration has no effect on the drug action.

atrial and ventricular dysrhythmias

538
Q

Which antidysrhythmic drugs show use dependence

A 
class IA
class III
539
Q

describe the affinity of class IB antidysrhythmic drugs

What does this mean

A

have greater affinity for the inactivated
than the activated states.

therefore influenced by length of AP

540
Q

How does the rate of dissociation of class IB antidysrhythmic drugs change

why

A

rate of dissociation during diastole decreases if the membrane potential is depolarised (because of
the dependence of recovery from local anaesthetic action on the membrane potential).

As the
membrane repolarises and the drug dissociates, its effect is removed

541
Q

When are IB antidysrhythmic drugs most effective

A
  • At high rates of firing
  • Where the diastolic (i.e. resting membrane potential) is depolarised
  • In the parts of the heart where the action potential is the longest
542
Q

Describe association and dissociation of class IC drugs

What does this mean they are good at

what does it also mean

A

very slow both to associate and dissociate.

This means that they are very good at suppressing ectopic beats.

However, because of their
extraordinarily slow kinetics they suppress almost everything else as well.
They are pro-dysrhythmic

543
Q

What are Class II antidysrhythmic agents - general effect?

A

ß1 antagonists (ß-blockers) and so decrease the effects of catecholamines on
the heart
(negative inotropic and chronotropic effects)

544
Q

When are Class II antidysrhythmic agents used

eg

A

in dysrhythmias where the tissue abnormality leads to increased excitability.

eg: myocardial infarction (in which the myocardium can become sensitized to catecholamines) where catecholamines can produce enough enhanced inward current to produce
APs and resultant ectopic foci.

545
Q

what drugs can be used in dysrhythmias where the tissue abnormality leads to increased excitability

A

ß1
antagonists (ß-blockers)

cardiac glycosides

546
Q

Can some antidysrhythmic drugs fit into >1 category

A

Some ß-blockers (class II) have other antidysrhythmic effects.

D and L-propranolol have Class I actions
(although only L-propranolol is a ß-blockers)

sotalol has Class III actions.

547
Q

Name a Class III antidysrhythmic agents

A

amiodarone

548
Q

What do Class III antidysrhythmic agents do

A

prolong the action potential and thus also the refractory period and they
probably do this by inhibiting the K+
currents that result in repolarisation.

may also
affect the inactivation of Na+
channels, prolonging inactivation and thus lengthening the AP. This helps to prevent re-entry and circus dysrhythmias

549
Q

Does amiodarone inhibit inward or outward currents

A

both

550
Q

How is amiodarone inhibition of inward Na+ and Ca2+ currents enhanced

What is the result

A

in a use dependent manner and in a
manner depending upon the voltage at which channels become de-inactivated.

suppression of excitability and conductivity in both I(Na) and I(Ca) dependent cardiac tissues

551
Q

The inhibition of inward Na and Ca currents by amiodarone is greater in which tissues

A

in the tissues stimulated at higher frequencies and in those with less negative
resting membrane potential

552
Q

Which outward K+ channels are inhibited by amiodarone

A

depends on amount of amiodarone present

553
Q

When would amiodarone cause shortening of AP duration

A

Action potential duration would be shortened if the inhibitory
action of amiodarone on the inward current is greater than on the outward current, and vice versa

554
Q

What are Class IV antidysrhythmic agents

Name one

A

These are Ca2+-channel antagonists that are selective for the myocardium

verapamil

555
Q

verapamil is an example of which drug

A

Class IV antidysrhythmic agent

These are Ca2+-channel antagonists

556
Q

Why are Class IV antidysrhythmic agents useful for many kinds of dysrhythmia

A

Ca2+

channels are ubiquitous in the heart

557
Q

Why must Class IV antidysrhythmic agents not be taken excessively

A

Ca2+ entry is important for producing the excitation-contraction coupling in cardiac muscle so excess may inhibit contraction

558
Q

Why arent class IV anti dysrhythmic drugs given when cardiac function is severely compromised

A

Ca2+
entry is important for producing
the excitation-contraction coupling in cardiac muscle so these drugs could inhibit contraction which would not be good after a serious MI or in cardiogenic shock

559
Q

Are all Ca2+ channel blockers useful as antidysrhythmic agents

A

no some Ca2+ channel blockers, like nifedipine, are not effective as antidysrhythmic agents but
may find use in myocardial salvage by decreasing Ca2+
loading of damaged tissue (which leads to cell
death).

Their vasodilator effects will also decrease myocardial oxygen demand

560
Q

How does verapamil affect myocardial oxygen demand

A

the slowing of the heart it also produces will also decrease oxygen demand

561
Q

How do ß-blockers affect myocardial Ca2+ influx

A

decrease Ca influx

562
Q

Name 2 drug types that do not fit into the Vaughn Williams classification but can be used for angina

A

adenosine

cardiac glycosides

563
Q

What is the mechanism of action of adenosine in dysrhythmia

A

acts on A1 receptors in the AV node. This is coupled via Gi and activation thus reduces cAMP.

net result is activation of IK-ACh

adenosine thus
hyperpolarises cardiac pacemaker and conductive tissue

564
Q

Which dysrhythmias can adenosine be used to treat

What is an advantage of it in these circumstances

A

for certain
supraventricular tachycardias

its short half-life can have some advantages

565
Q

How do cardiac glycosides act to treat angina (3)

A

by increasing vagal activity through an action in the CNS

inhibition at the AV node (so slowing AV conduction).
also affects atrial refractory
period

566
Q

Which drugs in the Vaughn Williams classification are pro-dysrhythmic

A

Class IC

The American ‘Cardiac arrhythmia suppression trial’ (CAST) of 1989 showed these drugs decreased chance of survival in comparison to placebo
The results mean that Class IC drugs are only used in very unusual circumstances now

MoDA (6 decks)

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