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
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
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
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
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
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
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
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)
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
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
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
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
13
Q
Why are local anaesthetics sometimes called membrane stabilising drugs
A
They inhibit the propagation of action potentials
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
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
16
Q
Give five ways to administer local anaesthetic
A
Surface Anastasia
Infiltration Anastasia
Nerve block
Epidural Anastasia
Intrathecal Anastasia
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
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
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
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
21
Q
What does quaternary local anaesthetics mean
A
Permanently charged
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
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
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
25
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
30-50% are inactivated
By driving the membrane potential beyond -80 mV
26
Describe the experiment of Hille when testing sodium channel activation at very negative voltages
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
27
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?
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
28
Name three toxins that act on the voltage gated sodium channel
Tetrodotoxin
Batrachotoxin
Scorpion toxins
29
Describe tetrodotoxin
Name a related toxin
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
30
Mutations in which part of the voltage gated sodium channel leads to loss of tetrodotoxin (TTX) binding
Glu387 in the S6 segment of domain I
31
True or false
TTX is considerably less effective on cardiac sodium channels
Explain
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
32
Where does batrachotoxin come from
What about TTX and saxitoxin
The skin of a Colombian tree frog
TTX- puffer fish organs
Saxitoxin - marine dinoflagellates
33
Describe the action of batrachotoxin!
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
34
Which toxins act in the same way as batrachotoxin
Aconitine and veratridine (plant alkaloids) - can cause
Pyrethrin insecticides and DDT act similarly in insects
35
What do you scorpion toxins contain
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
36
How is the VG Ca2+ channel similar to the Na+ channel in the heart
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
37
How are the α2 and δ subunits of the cardiac Ca VG channel related
α2 and δ are linked by a disulphide bridge but both are from the same gene
38
What are the principal drugs that act on voltage gated calcium channels in the heart? Give eg (3)
Categorise then
Dihydropyridines (eg nifedipine) and non-dihydropyridines:
Phenylalkylamines (verapamil)
Benzothiazepines (diltiazem)
39
What are the two types of voltage gated calcium channels which are of direct relevance in the heart and cardiovascular system
L (long) and T (transient) type
40
Compare the amount of depolarisation required to activate L and T type calcium channels
L: depolarisation of >30mV
T: 10-20 mV
41
Where are L type channels found
What do they do
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
42
What is the single channel conductance of L-type calcium channels in the heart
How long do they stay open for and inactivate
22-27pS
relatively long time and do not inactivate rapidly do so slowly
43
How is L-type calcium channel activity enhanced in cardiac cells
Via the action of adrenaline and noradrenaline which lead to phosphorylation of the channels
44
Which channel type do calcium channel blocking drugs of the cardiovascular system target
L type
45
Describe the opening and in activation of T type channels
What is the channel conductance
Open transiently and show rapid inactivation
8pS
46
What are LVA Ca2+ channels
Low voltage activated calcium channels (T type)
47
Where do T type channels occur
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
48
Generally what happens if potassium channel is open in normal cell
What type of potassium channel do cardiac and other excitable cells have
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
49
What determines the resting membrane potential in atrial and ventricular cells
The membrane having high permeability to K+ (ie Is dependent on the activity of the potassium channel)
50
What is the dual role of potassium channels in the heart
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
51
What is the shaker mutant a polymorphism of
A voltage gated potassium channel isolated in fruit flies
52
Describe the Shaker family voltage gated potassium channels in the heart
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
53
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
Voltage gated sodium channels arose from the potassium channel gene through gene duplication
54
What are the 2 types of inactivation showed by VG K+ channels
N-type and C type
55
Describe N type inactivation
“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
56
Describe C type inactivation
Slower inactivation of K+ channels
Result of movement of residues near the extracellular surface of the pore
57
Which K+ current is most important for the maintenance of the cardiomyocyte resting potential
Ik1 current (inward rectifying)
58
What happens if all the channels conducting the Ik1 current are open?
potassium is free to move across the membrane throughout the action potential
59
How much time do cardiac cells spend in depolarisation?
Why is this important?
50%
without some protection theey would lose lots of K+ through the resting potential type K+ channels
60
When is the outward driving force highest for K+ during the AP?
Why do we need to know this/
during depolarisation
as cardiac myocytes spend 50% of their time depolarised, inward rectification is needed to prevent mass K+ loss
61
How many transmembrane domains do channels carrying the Ik1 current have?
What family do these channels belong to?
2
Kir
62
Describe how Kir channels work in the heart
conduct inward K+ v effectively at hyperpolarised potentials but close at depolarised potentials, preventing an outward K+ current
63
True or false:
| inward K+ rectification is due to intracellular Mg2+ lodging in the pore
True but it is not solely due to Mg2+ - intracellular polyamines (esp. spermine) are of great importance
64
What is the valency of spermine
tetravalent
65
Is inward rectification only in the heart?
no they are common to many types of K+ channels in many tissues (some show both VG and inward rectification)
66
Other than the heart, name an organ which shows K+ inward rectification and state the reason for it being present
liver, kidney
purpose is unclear as these tissues never depolarise
67
Is the Kir channels carrying Ik1 the only inward K+ rectification in the heart?
No there are channels that carry currents such as I(K-ACh) and I(K-ATP) which are part of the Kir family
68
Describe the I(K-ACh) current (3)
sensitive to ACh
mediated by M2 receptors
hyperpolarises cardiocytes
69
Which channel carries the I(K-ACh) current
Kir3.1
or
HGIRK1 (Human G-protein-activated Inward Rectifying K+ Channel)
70
Describe the I(K-ATP) current
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
71
How are K(ATP) channels used pharmacologically?
influenced by sulphonylurea drugs to stimulate insulin secretion in T2 DM
present in vascular smooth muscle so targeted for hypertension
72
How does resting potential differ across the heart?
SNV and AVN: -60mV
| Ventricles: -80mV
73
How are I(K-ACh) channels activated
M2 activated and βγ subunits couple directly to the channel, opening it
74
What factors affect the shape of the different cardiac APs
resting potential
| expression of channel proteins
75
Give a cause of SADS
Long QT syndrome - heart suddnely goes into ventricular fibrillation
76
Give some conditions that SADS patients can have
hypertrophic cardiomyopathy
dilated cardiomyopathy
long QT syndrome
77
Why may the QT interval be extended
pharmacologically by some antibiotics (eg Clarithromycin) and antipsychotics
78
How do channels producing the If behave
similar to inward rectifiers - open on hyperpolarisation and close on depolarisation
79
How do If channels differ from Kir channels
channels for If are equally permeable to K+ as Na+
80
channels for If are equally permeable to K+ as Na+. What does this mean upon hyperpolarisation of the cell?
Na+ begins to enter, leading to a slow depolarisation, which will cause VG Na+ to open when the threshold is reached
81
What us the main difference bwteen pacemaker cells and myocytes
the presence of the If and the absence of VG Na+ current
82
What do Ca2+ channels do in the cardiac AP
L and T type channels generate the peak if the nodal AP
83
What do VG K+ channels contribute to the cardiac AP
Repolarisation
84
What is the name of the channels underlying the If
HCN
| Hyperpolarisation-activated and Cyclic Nucleotide gated channels
85
what is the structure of HCN channels
How are they activated specifically?
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)
86
Where is HCN1 present
brain and heart
87
what are HCN2 and HCN4
HCN subunits most abundantly expressed in the heart
| HCN2- throughout the heart; HCN4- Purkinje fibres and pacemaker regions
88
What does SNS action do the heart
positive inotropic and chronotropic action
89
What must any change to heart rate be mediated by
the potentials produced by the SAN
90
How do catecholamines affect rhe heart `
ACh?
increase rate of production of pacemaker potentials
ACh reduces the rate
91
How does beta AR stimulation affect the heart
What opposes this?
leads to a rise in [cAMP]i
M2 receptor stimulation
92
How are beta ARs and muscarinic receptors distributed in the heart?
beta ARs are on nodal cells and on the ventricular cells
muscarinic are mainly confined to the nodes
93
What is an increase in L and T type Ca2+ currents mediated by
How can this be mimicked? Blocked?
cAMP
administration of adrenaline or isoprenaline
blocked by propranolol (non specific beta blocker) or atenolol (specific beta 1 blocker)
94
In the heart, beta 1 ARs are coupled to Gs, leading to a rise in cAMP. Which Ca2+ channel is this important for?
L type - modulates pacemaker potential and enhances Ca2+ entry into cells for excitation-contraction coupling
95
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?
quite slow - latent period of 5s and then takes 30s for current to reach max.
yes - reversal is also slow
96
Why is the stimulation of cardiac Ca2+ channels slow?
must be phosphorylated by PKA so whole process involves cAMP and then PKA stimulation. - much slower than ligand gated ion channel
97
How can you mimic the effect of beta1 stimulation?
using cholera toxin (stimulates G protein) or forskolin (stimulates AC)
98
What covalent modification happens to SERCA2 during the cardiac AP? Name another molecule that also undergoes this modification
PKA phosphorylates SERCA2 and phospholamban
99
How do catecholamines affect the If
shift the voltage at which If is activated to a more positive value
100
How do cAMP and isoprenaline affect delayed rectifying K+ channels
enhances repolarisation, shortening the AP having a positive chronotropic effect
101
How do M2 receptors affect cAMP
inhibit its formation so has the reverse effect of catacholamines
102
True or false
| Over activation of M2 can stop the heart
true - such as in excessive vagal simulation
103
How does M2 receptor activation affect Ca2+ in the heart
Ca2+ currents are reduced, leading to a reduced rate but NOT reduced contractility because M2 are largely confined to the nodes
104
How does M2 stimultaion affect If
the potential at which If is activated is made more negative, meaning pacemaker produces more widely spaced potentials
105
Is the I(K-ACh) current influenced by M2
yes - directly
| stimulation hyperpolarises the cell, making it more difficult to elicit APs
106
What is an ectopic pacemaker
also called an ectopic focus - this is a pacemaker at a site other than the SAN
107
What happens when waves of depolarisation in the heart collide?
Is this a bad thing?
they extinguish each other
these extinctions are important for normal cardiac function
108
Why may electrical organisation problems arise in the heart ?
SAN not operating properly, allowing ectopic foci to form
myocardium is damaged, slowing conduction velocity
109
What is the issue with conduction organization if the myocardium is damaged?
slowed velocity means impulses are no longer coordinated .
| Inappropriate excitation occurs as an impulse might excite a tissue that would normally be refractory
110
what is the commonest reason for conductive abnormalities
myocardial infarction/ heart attack
111
What happens to conduction in a heart attack
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
112
What happens in angina pectoris
myocardium becomes ischaemic and cannot operate efficiently but all tissue can conduct
113
Describe Wolff-Parkinson-White syndrome
```
congential abnormal (extra) conducting fibres
accelerates transmission from atria to ventricles
```
114
Can dysrhythmias be caused by mutations in ion channels
yes - eg Long QT Syndrome - more than 150 different mutations haev been indentified in seven LQT genes
115
Which 3 gene mutations account for 95% of identified mutations causing Long QT syndrome?
What can mutations in these genes do?
LQT1 (43%)
LQT2 (45%)
LQT3 (7%)
modify cardiac AP and voltage gradient in conduction tissues especially at ventricular level. Environment is also important
116
What is important to note about the Vaughan Williams classification of antidysrhythmic drugs
they are based on the effect of the drug not the type of drug itself
117
What are the different classes of antidysrhythmic drugs according to Vaughan Williams
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
118
Give an example of each of the Vaughan Williams antidysrhythmic drug classes?
```
IA: quinidine, procainamide
IB: Lidocaine
IC: flecainide
II: propranolol, atenolol
III: amiodarone
IV: verapamil
```
119
Describe Class I antidysrhythmic drugs
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
120
Which antidysrhythmic drugs block Ca2+ channels
Class IV eg Verapamil
121
What is cardiac failure?
the heart failing to maintain an adequate circulation for sufficient tissue perfusion
122
What is the range of volumes the heart can pump in a healthy condition
2-25 litres per minute
Normal is 5L/min
123
If the right side of the heart is failing, how does it manifest?
Peripheral oedema and ascites (fluid forced out of the liver into the abdominal cavity)
124
What happens in left heart failure?
pulmonary oedema, leading to cardiogenic shock
125
How is the kidney involved in heart failure
insufficient perfusion leads to renin secretion and thus fluid retention, increasing MSFP
126
Which side heart failure leads to cyanosis? What other symptoms are common in this type?
both
| breathlessness and fatigue
127
Does heart failure develop rapidly?
It can do in myocardial infarction but can also develop slowly after excessive demands on the heart
128
Give 11 reasons for excessive demands being put on the heart
```
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
```
129
What are the 4 classes of cardiac failure according to the NY Heart Association
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
130
What is the prognosis for people with Class 4 heart failure
very poor
131
What is drug treatment for heart failure based upon?
increasing contractility
increasing rate
reducing heart's work load(by reducing MSFP)
132
Give the different types of drugs that can be used for heart failure (5)
```
cardiac glycosides
Dobutamine (ß1 agonists) for rapid effect in acute cases
Beta-blockers
Inodilators
ACE inhibitors
```
133
Where does the cardiac glycoside digoxin come from
foxglove extract
been used for 200 years
134
What are cardiac glycosides more commonly used for now?
as antidysrhythmic drugs
135
What is ouabain?
a very potent cardiac glycoside that is not used clinically
136
What do cardiac glycosides do
inhibit Na+/K+ ATPase
137
What happens to the Ca2+ in the heart cells during diastole?
How is this achieved?
Ca2+ leaves to bring about relaxation
NCX
138
Why is the Na+/K+ pump important for Ca2+ removal in cardiomyocytes?
Na+ Pump creates a conc gradient that the NCX uses to extrude Ca2+
139
What is the stoichiometry of NCX
3 Na+ in: 1 Ca2+ out
140
How do cardiac glycosides affect [Na+]
increase [Na+]i from 1mM to 1.5mM
141
What, in cardiomyocytes, does [Ca2+]in depend on?
[Na+]in to the third power - a small change in intracellular Na+ wll produce relatively large charge in intracellular Ca2+
142
Does the number of Na+ pumps change in disease?
Yes the number of pumps deceases in ischaemia
143
Should you use ß1
| agonist to treat heart failure (3)
NO - while it does have a positive inotropic effect, this increases O2 demand.
They also increase rate, revealing dysrhythmias
may also precipitate/ potentiate hypertension
144
Are ß1
| agonists ever used to treat heart failure?
yes
Dobutamine (ßl
-selective analogue of dopamine) is used for acute failure as its positive inotropic effect >> chronotropic
used for shock or to improve CO after open heart surgery or in heart failure in absence of hypertension
145
Why are ß blockers used in heart failure?
homeostatic response is to increase SNS output but this gradually decreases heart function so blocking this is important in chronic heart failure
146
Where does the key to the potentially harmful effect of chronic adrenergic stimulation on myocardial function lie?
desensitization and downregulation
147
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
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
148
Describe experiment where the toxicity of excess NA was tested
1990s - exposed mammalian cardiomyocytes to catecholamines, resulted in cell death
Stimulation with NA resulted in spontaneous contractions and then hypercontraction and cell death
149
How do different AR blockers affect heart health in cardiac failure
á-adrenoceptor antagonist (phentolamine) - slight blocking action on the toxic effects of NA
```
beta antagonist (propranolol) led to greater
attenuation
```
150
Which AR antagonists are used in heart failure
Name 2
3rd generation ß1 blockers
eg bisoprolol and carvedilol
151
What must you be careful of when using beta blockers in heart failure
they must be carefully titrated due to the risk of overinhibition
152
What are inodilators
inotropic vasodilators
ie phosphodiesterase inhibitors
153
What does PDE do
Therefore, what do inodilators do to the levels of molecules in the cell
catalyzes breakdown of cAMP
increases cAMP levels, mimicking effects of ß-receptor stimulation
154
True or false:
| Inodilators can lead to arrhythmias
True because they mimic beta AR stimulation
155
Name an inhibitor drug for each of the 5 types of PDE
```
I: phenothiazines
II: N/A
III: milrinone *
IV: rolipram
V: dipyridamole*, sildenafil *
```
156
What kind of drug is sildenafil?
Type V PDE inhibitor
157
Which inodilator is most commonly used in heart failure?
What type of PDE does this inhibit?
What is a caveat of using this drug?
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
158
How do inodilators cause vasodilation?
What is the benefit of this?
in smooth muscle, increased [cAMP], from PDE III inhibition, leads to vasodilation
decreases afterload on heart
159
What durg type are non selective PDE inhibitors?
methylxanthines (eg caffeine and theophylline)
160
Methylxanthines are non selective PDE inhibitors. What else do they do?
What does the combination of these effects lead to?
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
161
Which of the effects of methylxanthines are most important in the CNS ?
adenosine receptor antagonism
162
Which inodilator has revolutionized canine dilated cardiomyopathy in Dobermanns ?
What class of drug is this drug part of?
Pimobendan
'calcium sensitizers'
163
What do Ca sensitisers do?
sensitise and increase cardiac Ca2+ binding efficiency to troponin without increased energy consumption
also inhibit PDE III so cause vasodilation
164
name a calcium sensitiser in human clinical practice
levosimendan (not licensed in the UK)
165
Name a PDE used to treat mental illness
phenothiazines
166
What is the muscle specific SR Ca2+ ATPase that leads to relaxation
SERCA2
167
What is phospholamban
an endogenous muscle specific SERCA2 inhibitor
168
What is the key regulator of the SERCA2/ phospholamban inhibitor
the SNS via beta AR activation and PKA
169
How does PKA affect the SERCA2/ phospholamban system
phosphorylates ryanodine, SERCA2, and phospholamban, allowing for intracellular Ca2+ transients with higher ampiltudes and and faster reuptake
170
What does PKA's phosphorylation of phospholamban do
promotes dissociation of phospholamban from SERCA2, relieving inhibition, allowing faster reuptake
171
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?
correcting Ca2+ transient by manipulating components phosphorylated by PKA may help recover contractility
172
The gene for which protein has been tested as a gene therapy treating heatr failure?
phospholamban
173
Describe the experiments assessing validity of phospholamban gene therapy for heart failure (2)
Result?
knock out mice or viral delivery of antisense phospholamban to cardiac cells
improved calcium handling and contraction but similar experiments were less successful
174
Describe a human example of depleted phospholamban
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
175
Describe the experiment assessing the effect of gene therapy on SERCA2 for treating dysrhythmia
What was the effect
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
176
What does lusitropic mean
producing cardiac relaxation
177
How are viruses used in possible SERCA2 gene therapies
use of adeno-associated virus vectors to introduce
| the gene for expression
178
What kind of therapy is very useful after a myocardial infarction?
What does this decrease the incidence of?
fibrinolytic therapy
arrhythmia
179
What is streptokinase
a 47kDa protein formed by haemolytic streptococci
180
Describe the action of streptokinase
binds plasminogen activator leading to the generation of plasmin and thus the degradation of fibrin in clots
181
What is plasmin
a protease hydrolysing Arg-Lys
| bonds
182
which protein does plasmin degrade>?
What else does it break down
fibrin
clotting factors II, V and VII
183
What is alteplase
why is it particularly beneficial
recombinant human tissue plasminogen activator
has greater activity on plasminogen bound to fibrin in clots, thus localizing their action
184
Why is low dose aspirin used in a heart attack
What is it often combined with
prevents further thrombosis
clopidogrel
185
Describe the action of clopidogrel
inhibits platelet aggregation by inhibiting the
| binding of ADP to its receptor on platelets
186
Why can't clopidogrel be used in everyone
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
187
What is the name of the gene that encodes the cytochrome that activates clopidogrel
What is this type of cytochrome called
CYP2C19
cytochrome P450
188
In patients with 2 non functional cytochrome P450 genes, what is combined with aspirin after a heart attack
ticagrelor (an ADP inhibitor)
189
Which receptor is needed for fibrinogen binding between platelets? Which drugs target these? Give an example
glycoprotein IIb/IIIa receptor
aIIb/b3 integrin antagonists
Eptifibatide
190
Describe Eptifibatide
cyclic heptapeptide inhibitor of the glycoprotein IIb/IIIa receptor
191
Other than eptifibatide, give 2 exmaples of aIIb/b3 integrin inhibitors
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
192
Which drug tends to be used with coronary angioplasty for coronary artery thrombosis
Abciximab
193
What is tirofiban used for
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)
194
What process is vitronectin involved in
cell adhesion and haemostasis
195
What is heparin
a naturalluy occurring anticoagulant produced by basophils and mast cells
196
Describe the action of heparin
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
197
What is heparin used for
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
198
Describe a drug class similar to heparin
low Mr heparins
| considered distinct from heparin
199
Why are low molecular weight heparins considered distinct from heparin (3)
their wider
application, subcutaneous route of admininstration and more predictable pharmacokinetics
(so are easier to use)
200
What is an undesirable effect of heparin
heparin induced thrombocytopenia as a development of low platelet count
201
How must heparin be administered
by injection
202
how can warfarin be administered
What does it do
orally
inhibits clotting
203
Give the mechanics of warfarin action (there are 7 molcules affected)
inhibits synthesis of clotting factors II, VII, IX, and X
| inhibits synthesis of regulatory factors protein C, S and Z
204
Who is warfarin given to (3)
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
205
Why is dosing of warfarin comlicated
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
206
Which anticoagulant can be used as a rodenticide
warfarin
207
Why is warfarin a better rodenticide than other bait based pesticides?
What is a drawback of warfarin?
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
208
Which thrombin inhibitor is used in patients with atrial fibrillation and one other risk factor for a stroke
dabigatran
209
Why is dabigatran used to treat atrial fibrillation
this condition can lead to clot development/
210
How can dabigatran be used in the short term
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).
211
Which clotting factor for which a whole set of drugs is named
Give 3 examples
Xa
these inhibit Xa directly
rivaroXaban
apiXaban
edoXaban
212
Name an indirect inhibitor of Xa
What is it used to treat
Fondaparinux
acute coronary syndromes
213
What is argatroban
Which patients is it used in
synthetic direct thrombin inhibitor - this is used if patients suffer from HIT
214
What is bivalirudin
a hirudin analogue
215
What is hirudin
thrombin inhibitor found in saliva of the medicinal leech
216
What kind of drug is danaparoid
Which patients is it used in?
an indirect inactivator of Factor Xa and a direct inhibitor of
thrombin activation of Factor IX
Mainly used in patients who have had HIT
217
What can excessive clot lysis lead to
How can this be treated
severe bleeding
with tranexamic acid (TXA) which competitively inhibits plasminogen activation
218
Other than excessive clot lysis, when may tranexamic acid be used?
to suppress bleeding seen in traumatic injury or post partum
219
Which part of the LoH is impermeable to water?
thick ascending limb
220
What do diuretics do
What is the effect
increase urine output
reduce ECF volume
221
True or false
| All diuretics promote natriuresis
true - they all increase Na+ excretion
222
What is the difference between diuresis that occurs after drinking larger amounts of liquid and taking a diuretic drug
Diuretic drugs produce an increase in the
| excretion of both solutes and water.
223
What is the way the kindey can activately reabsorb K+ in the DCT and collecting duct
K+/H+ ATPase
224
What are loop diuretics
AKA?
eg?
diuretics that act on the LoH
AKA high ceiling diuretics
furosemide and bumetanide
225
Why are they called high ceiling diuretics
they have the capacity to cause a very high rate of diuresis (up to 4 litres/day)
226
What type of drug are furosemide and bumetanide
sulphonamides - a type of loop diuretic
227
How were sulphonamides developed
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
Describe the action of furosemide
Blocks NKCC2 of the thick ascending limb of the LoH
229
How does the [loop diuretic] differ from the plasma to the thick ascending limb?
10-30x stronger in the ascending limb because it is actively secreted into the proximal tubule
230
True or false
| Loop diuretics only affect the NKCC in the nephron
false
| also weakly inhibits carbonic anhydrase
231
At peak activity, how much of the filtrate can loop diuretics cause to be excreted?
Does this value change?
15-25%
On repeated administration the effect is
reduced because the decrease in extracellular fluid volume leads to enhanced reabsorption in
tubules
232
In which emergency condition are loop diuretics particularly useful
acute heart failure
because it can lead to such a massive reduction in ECF
233
How long does furosemide take to act if administered IV
How does an oral dose differ?
10 mins
extended to 1-1.5 hours
234
True or false
| The diuretic effect of furosemide is the most important in acute heart failure
false
| Quickly causes vasodilation which rapidly decreases RAP
235
How does the vasodilator effect of furosemide aid the effect on the nephron
increases renal blood flow without changing GFR (decreases the fraction of the blood flow that is filtered at the glomerulus)
236
Give 4 potential problems with loop diuretics
hypokalaemia
concurrent alkalosis
Ca2+ and Mg2+ loss
Uric acid excretion is decreased
237
How can loop diuretics lead to hypokalaemia
continued administration means the increased Na+ load in the distal tubule results in increased K+ loss
238
How can hypokalaemia from loop diuretics be avoided
K+ can be replaced by exogenous short term K+
-releasing compounds
or loop diuretics can be given with K+-sparing diuretics
239
why can concurrent metabolic alkalosis occur because of loop diuretics
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
Where are Ca2+ and Mg2+ usually absorbed?
Why is their loss increased after taking loop diuretics
PCT usually absorbs 80%
mechanism is unknown
241
What does the decreased uric acid excretion lead to while taking loop diuretics
gout
242
What do the symptoms of gout arise from
xs production of purines, leading to formation of sodium urate crystals in synovial tissue (esp in joints)
243
What is used to treat gout? What is the drug mechanism?
probenecid
competes for same carrier as uric acid in PCT, inhibiting uric acid reabsorption
244
What are the commonest Thiazide diuretics
hydrochlorothiazide
| Bendroflumethiazide
245
Which of the action s of Thiazide diuretics is the same as loop diuretics (2)
inhibition of CA
vasodilation
246
What do Thiazide diuretics do overall
inhibit formatuion of dilute urine but not a concentrated urine
247
Where is the site of action of thiazide diuretics
thick ascending limb or in the distal tubule
248
What is the mechanism of thiazide diuretic action in the DCT?
How was this discovered?
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
Describe the hypotensive effects of thiazide diuretics when given for hypertension
initially decrease BP from diuretic effect but later there is direct action on blood vessels
250
Give 5 potential problems with thiazide diuretics
same as furosemide -hypokalaemia
metabolic alkalosis
decreased uric acid excretion
increase Mg2+ excretion but decrease Ca2+ excretion
251
What is the average fall in plasma K+ when Thiazide diuretics are administered
When would this be a big problem
0.7mM
if thiazides were combined with cardiac glycosides, as lower [K+]plasma can potentiate action of cardiac glycosides
252
Which diuretics do not have the side effect of K+ loss
Potassium-sparing diuretics
diuretics that don't have the K+ loss of loop diuretics and thiazides
253
What are the 3 main potassium sparing diuretics?
What is the mechanism of their action
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
How do amiloride and triamterene work
What level is the diuretic effect
prevent Na+ reabsorption by blocking apical Na+ channels
weak but K+ loss is decreased
255
How can we prove amiloride only acts on one side
amiloride only blocks Na+ transport when applied on the apical side
256
How does spironolactone work
antagonist of aldosterone action by competing for binding on the aldo receptor in the cytoplasm
257
How does aldo initiate a response
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
How can the action of aldo be proved
an aldosterone-induced increased in C14-amiloride binding
259
What is spironolactone metabolised into and where does it occur
into canrenone in the liver
260
True or false
| The effects of spironolactone are thought to be due to its metabolism
True
| K+-canrenone works as a K+ sparing diuretic
261
When is the effect of spironolactone significant
only when the DCT is under influence of aldo
262
What are potassium sparing diuretics often used in conjunction with
thiazides or loop diuretics to counteract hypokalaemia
263
How fast is the rate of onset for diuresis after spironolactone is administered
slow as mechanism depends on turnover of Na+ channels
264
Are Na+ channels in epithelial cells the same as in nerves?
Why is this important
NO - they are no voltage gated and have different structure
different susceptibility to drugs
265
What is the major drug in the carbonic anhydrase inhibitor diuretic
acetazolamide
266
What were the first diuretics to be introduced
What is the aim of them
CA inhibitors
To inhibit NaHCO3 reabsorption in the PCT and DCT by decreasing amount of H+ available
267
Where is CA located inthe kidney
brush border of PCT and intracellularly
| only intracellularly in the DCT
268
What is the net NaHCO3 reabsorption driven by
Na/K pump
269
How is urine pH affected by CA inhibitors
pH increases as HCO3- content increases
270
How effective are CA inhibitors as diuretics
v weak diuretics
mainly used to treat glaucoma
271
How are CA inhibitors used to treat glaucoma
suppress HCO3- secretion, preventing formation of aqueous humour in the eye
272
How can the action of CA inhibitors be controlled
self limiting because excess HCO3- loss leads to metabolic acidosis
273
What can acetazolamide be used for other than as a diuretic
acclimatization to high altitudes
| alleviate sleep apnoea at altitude
274
Which type of diuretic has the simplest function
osmotic diuretics eg mannitol
275
How do osmotic diuretics work
small Mr filtered at glomerulus but not reabsorbed
Draw in water, increasing urine volume level
Also decrease Na+ reabsorption by decreasing [Na+]
276
When are osmotic diuretics usful
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
What can mannitol be used for acutely
to rapidly reduce intracranial and intraocular pressure
useful in cerebral oedema
278
How does mannitol cross the BBB
it cannot
279
How can diuretics affect blood pressure
reduce blood pressure
280
What are the 3 key hormones of blood pressure control
ATII
aldosterone
ANP
281
A rise in what second messenger leads to renin release
cAMP
282
Name 3 things which reduce renin release
adenosine (acting on A1 receptors which inhibit cAMP formation)
ANP (via cGMP)
negative feedback by ATII (IP3 mediated response)
283
Where is angiotensinogen produced
it is a plasma globulin manufactured in the liver
284
Describe ACE
membrane-bound carboxypeptidase and is
| most abundant on the endothelium and smooth muscle of the lung
285
true or false
| ACE is only found in the lungs
false
| also found in kidney and other organs
286
What is kininase II
AKA Angiotensin converting enzyme
breaks down bradykinin
287
How is antagonism of the renin angiotensin system mainly achieved
Give 3 examples
ACE inhibitors
ramipril
lisinopril
perindopril
288
What is saralasin?
ATII partial agnoist
289
What is the issue with saralasin
it is a peptide so is not suitable orally hence is not competitive with other hypertensive drugs
290
Have we developed any non peptide ATII antagonists
yes eg losartan
291
what does losartan act on
AT1 receptor (a receptor for angiotensin II - DO NOT CONFUSE WITH ANGIOTENSIN I)
292
What is the role of AT2 receptors
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
What kind of heart failure should ACE inhibitors be useful for theoretically
when associated with high renin levels
294
Why are ACE inhibitors beneficial in heart failure
useful in ,old heaty faikure becaise the failing heart activates renin so ACE inhibitors can reducce pre- and aferload
reduce TPR not BP
295
How can ACE inhibitors decrease TPR but not BP
heart can compensate by Increasing CO
296
Which drugs are ACE inhibitors often combined with
Why can this be useful
diuretics
reduced aldo should help avoid hypokalaemia
297
Which end does ACE cleave to form ATII
How can ATIII and ATIV be formed
C terminal
successive cleavage of the N terminal end
298
What do ATIII and ATIV do
Have same affinity for AT1 and 2
intracerevroventricular injection of either increases ADH release and increases BP
299
Can ATII be converted into ATIII
What are the clinical implications of this
yes by brain aminopeptidase-A
aminopeptidase A could be used as a central theerpeutic target for hypertension
300
Where does ATIV act primarily
brain - innvoled in learning, memory and long term potentiation
301
Which enzyme produces AT IV
aminopeptidase-N
302
Which receptor may be activated by AT IV
AT4
303
How are AT4 receptors different from AT1 and 2
they are
| transmembrane-located enzymes called insulin-regulated membrane aminopeptidase (IRAP).
304
Are AT4 receptors widely distributed?
Yes - not just in the brain
305
Clinical application of AT4 receptors
memory enhancement, eg in Alzheimer's disease
306
True or false
| Hypotension is dangerous with any ACE inhibitor
true - risk of renal failure is increased by the blockade of efferent arteriole constriction (mediated by ATII)
307
Describe bradykinin
short peptide
potent natriuretic
renal vasodilator
308
Where in the kidney can kininogen and kallikrein be found
early DCT
collecting duct is also rich in kininogen as well as B2 bradykinin receptors
309
Where is bradykinin metabolised in the kidney
PCT which is rich peptidases which can metabolise it
310
What is the role of the kallikrein-kinin system in the kidney
minimal noramlly
but if high Na+ reaches the DCT, kallikrein is released and bradykinin is formed from kininogen, inhibiting Na+ reabsorption
311
How does ANP act
```
via a membrane-bound
guanylate cyclase (GC-A) receptor to form cGMP with the aim of reducing BP and blood volume
```
312
True or false
| ANP is a directly acting vasodilator
true but does also reduce NA release
313
How does ANP promote diuresis
Where is its main effect
increasing GFR
decreasing Na+ reabsorption
collecting duct
314
How does ANP effect renin
decreases it release
315
Which drugs affect ANP
There are no useful drugs acting to influence ANP (or its receptors)
316
Are defects in the ANP system involved in hypertension
not really
| however, mice lacking the GC-A gene are hypertensive (which is not made worse by a high-salt diet).
317
Hypertension is rarely caused by a single cause. Give one exception of a cause of hypertension and what it is
One exception to this is phaeochromocytoma (an adrenaline-secreting tumour of chromaffin cells in the adrenal medulla)
318
how common and dangerous is phaeochromocytoma
not common but when it does occur it is very dangerous
319
what is it called when the majority of renal artery disease have no obvious single cause
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
what is the approx diastolic and systolic pressure of a young adult, and give the mean arterial pressure
distolic pressure- 80mm Hg
systolic pressure - 120mm Hg
mean arterial pressure - around 96mm Hg
321
what is the broad pressure in mild hypertension for diastolic and systolic
diastolic pressure is > 90 mm Hg, systolic > 140 mm Hg
322
give the 6 mechanisms that are most significant involved in development of essential hypertension
```
Cardiac output
• Peripheral resistance
• The renin-angiotensin-aldosterone system and the kidney
• The autonomic nervous system
• The endothelium
• Vasoactive peptides
```
323
what must be reduced to reduce blood pressure
CO or TPR
324
what causes TPR?
arteriolar resistance
325
what changes does chronic smooth muscle contraction lead to?
thickening of the arteriolar vessel walls - possibly mediated by angiotensin - leading to an
irreversible rise in peripheral resistance.
326
What has been proposed about resistance 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
327
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
develops in a compensatory manner to prevent the raised
| pressure being transmitted to the capillary bed where it would affect cell homeostasis
328
Do NA and adrenaline have a role in essential hypertension
there is little evidence to support this
329
If there is little evidence for role of NA and adrenaline in the etiology of essential hypertension, are SNS blockers still useful?
yes they do lower blood pressure
330
name 2 vasoactive agents produced by the endothelium
Why is this important clinically
NO
endothelin
Dysfunction of the
endothelium has been implicated in human essential hypertension
331
What happens to NO in atheroma
endothelial NO production is compromised
332
Describe some of the effects of endothelin (3)
vasoconstrictor
may produce a salt sensitive rise in BP
activate renin - angiotensin systems
333
What suggests that endothelial dysfunction becomes irreversible once the
hypertensive process has become established.
Some antihypertensive therapy seems to restore impaired production
of nitric oxide, but paradoxically does not necessarily restore the impaired endothelium-dependent
relaxation.
334
Is the circulating renin angiotensin system thought to be responsible for the rise in BP in hypertension?
not directly
| hypertensive patients tend to have low levels of renin and angiotensin II
335
Name 2 vasoactive peptides
ANP
| Bradykinin
336
What inhibits bradykinin
ACE
337
Apart from any effect on angiotensin, why might ACE blockers lower BP
ACE inhibits bradykinin so ACE inhibitors block bradykinin's inactivation
338
If circulating renin-AT systems aren't important in hypertension, why is understanding of renin and AT still important?
local renin-AT paracrine systems also control BP
339
Where have local renin AT systems been reported
What are these systems important for?
in the kidney, the heart, and the arteries
regulating regional blood flow
340
How many genes have been found to cause hypertension and hypotension
hypertension: 8
hypotension: 9
341
Name an inherited hypertensive mutation
Liddle's syndrome
342
Describe Liddle's syndrome
| what is it, what is the mutation, what is the result
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
What is a paracrine hormone
a hormone whose effects are confined to tissues in the vicinity of the gland secreting it
344
What is striking about the mutated gene products that have been shown to definitely be associated with hypertension
they all act on the kidney, altering net renal salt reabsorption
345
Give 3 pieces of evidence suggesting the key role of the kidney in the aetiology of essential hypertension
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
Name 7 antihypertensive drug types
Diuretics
ACE inhibitors
beta blockers
alpha 1 AR blockers
Ca channel blockers
K channel openers
Centrally-acting alpha2/I1 -agonists
347
What are the 2 phases of the effects of diuretics on hypertension
initially: decrease blood volume
latter: vasodilation
348
How long does it take for full hypotensive effect to take place when taking diuretics
up to 12 weeks
349
What is a common side effect of ACE inhibitors
(possibly severe) dry cough
350
When is it logical to use ACE inhibitors in hypertension
when plasma renin is high
351
How many hyper tensive patients respond to ACE inhibitors
50-75% mild-moderate
| hypertensives respond to ACE inhibitors
352
What is useful to combine with ACE inhibitors to reduce hypertension
diuretics
353
What is used to treat patients who are intolerant to ACE inhibitors
ARBs
354
Have beta blockers been used successfully to treat hypertension?
yes very much so
355
What kind of beta blockers are preferable to treat hypertension?
beta 1 specific are preferred over non- specific (non-specific can result in bronchoconstriction)
356
Name 2 b1 specific beta blockers
atenolol and bisoprolol
357
What is likely the cause of the effectiveness of b1 blockers in hypertension
Decreased cardiac output (as a result of ßl
blockade).
• Decreased plasma renin
• CNS action
358
How well does atenolol penetrate the CNS
How does this impact its effect on hypertension
not much as it is hydrophilic
it decreases blood pressure just as effectively as penetrant antagonists
359
Are beta blockers still the mainstay of hypertensive treatment?
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
Give 2 of the CNS side effects of beta blockers
insomnia
| depression
361
Are a1 ARBs used for hypertension
yes but are not frontline drugs
362
What is the best known example of a1 ARBs used to treat hypertension amongst veteran
pharmacologists
prazosin
363
What is the most used modern a1 blocker
doxazosin
364
How is the tone of arterioles usually controlled
via a1 AR sympathetic control causing vasoconstrictio
365
What might cause a non selective a1 blockade
What does this give
phentolamine
vasodilatation and
as a result a marked reflex tachycardia.
366
How does increased SNS activity affect renin
increases renin secretion
367
What does doxazosin do in hypertension
a1 AR blocker
dilates resistance and capacitance vessels
no marked tachycardia
368
why is there no marked tachycardia from doxazosin
lack of block of presynaptic á2
| -receptors.
369
What decreases SNS activity when doxazosin is administered
Blockade of CNS á1
- receptors modulates baroreceptor
reflex mechanisms
370
What is labetalol?
an unusual drug being an á1
, ß1
and ß2
antagonist (But more so ß than á).
371
What do Ca channel blockers act on
on L-type Ca2+
| channels
372
What effects do Ca channel blockers have other than their cardiovascular effect
mild diuretic effect, independent of any change in renal
| blood flow or GFR
373
What causes the mild diuretic effect caused by Ca channel blockers
Ca2+
channel blockade may inhibit aldosterone release which is
stimulated by angiotensin II
374
How do Ca channel blockers affect baroreflexes
antagonise baroreceptor
| reflexes, but this is most probably not important in long-term control.
375
what was the original dihydropyridine drug?
Is it still used?
nifedipine
yes but amlodipine is more commonly used
376
What is the most commonly used Ca channel blocker?
amlodipine
377
what is the only K channel opener in general use for hypertension
What is an example that is used in angina
minoxidil
nicorandil
378
Describe the action of K channel openers
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
What opposes depolarisation of ischemic cardiomyocytes
the fall in ATP opens the channels, opposing depolarisation.
380
What is a KCO used in severe refractory hypertension and what is it used with
Minoxidil with a ß-blocker and diuretic to
| counteract respectively reflex tachycardia and any increase in blood volume
381
What is a side effect of minoxidil
hirsutism
382
Which KCO can be used aesthetically?
minoxidil - has some use as a topical hair loss treatment
383
What does minoxidil work best on topically
How well does it work
How is it found now?
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
What are the archetypal centrally acting a2/i2 agonists
clonidine
| guanfacine
385
How was clonidine originally thought to act
by decreasing noradrenaline release via an
action on presynaptic á2
receptors in the CNS.
386
How can you administer clonidine to decrease bp
microinjection into ventrolateral medulla (brainstem)
387
Why is it effectobe to microinject clonidine into the ventrolateral medulla of the brainstem?
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
What usually acts on I1 receptors
What is this mimicked by?
catecholamines
imidazoline drugs (such as moxonidine)
389
Which is a more potent a2 agonist: clonidine or guanfacine ?
guanfacine - BUT has low efficacy as an antihypertensive
390
How does moxonidine act on hypertension
as a centrally acting antihypertensive but
has fewer side-effects than á2
agonists.
391
Generally, what is involved in the I1 receptor pathway?
G-protein coupling to specific transmembrane signalling
| pathways, leading to the generation of diacylglycerol and arachidonic acid.
392
Name a false transmitter used to treat hypertension
á-methylnoradrenaline
taken as á-methyldopa to be converted to á-methylnoradrenaline in vesicles of adrenergic neurons
393
How well does á-methylnoradrenaline act on different ARs?
less potent than noradrenaline on á1
receptors, but more potent on á2
.
394
What is a problem with centrally acting antihypertensive drugs
Sudden withdrawal leads to rebound but this is
| much less marked after withdrawal of moxonidine than after withdrawal of clonidine.
395
Which blood vessels does atherosclerosis affect
What is atherosclerosis colloquially described as
arterial
arterial 'hardening'
396
What is an atheroma
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
What is the etymology of atheroma
a (“lump of porridge” from “athera” - porridge in Greek)
398
How can atheromas change to more complex lesions
with underlying areas of cholesterol crystals, and also calcification
in more advanced stages
399
How can an atheroma lead to angina
What are 2 other scary outcomes of atheroma
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
What does chronic under perfusion of the myocardium lead to
What if it affects conductive tissue
congestive heart failure
dysrhythmia
401
What is the difference between arteriosclerosis and atherosclerosis
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
How does atherosclerosis affect the legs
claudication from insufficient blood supply to the legs in advanced disease
similar events can occur in other organs due to atheromas
403
What is an effectvie way to reduce incidence of serious events arising from atherosclerosis
What is the most common therapy to do this
reducing plasms lipids
to reduce blood cholesterol either through dietary changes or drugs
404
How is cholesterol transported in the blood
How does this relate to risk of atheroma
in lipoproteins
excessive low-density lipoproteins (LDL) especially predispose to atheroma
405
What are lipoproteins composed of
cholesterol intercalated in a phospholipid membrane and
cholesteryl esters.
apolipoproteins are associated with the lipid particle (different lipoproteins have different apolipoproteins)
406
What are the different apolipoproteins in
a) LDL
b) HDL
a) ApoB
| b) mainly ApoA
407
True or false
LDL seems to protect against atheroma development
Therefore how can you sum up the goal of atheroma drug therapy simplistically?
FALSE
In
contrast to LDL, HDL seem to be protective against atheroma development
decrease LDL and increase HDL (if possible)
408
How does LDL enter the hepatocyte
receptor mediated endocytosis
409
What does the bile produced by the liver contain
where is it secreted into
what happens to it
what does this mean
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
How is the enterohepatic circulation topped up
with newly synthesised cholesterol, or cholesterol that has been taken up by the liver, the source
being LDL.
411
Name 2 statins
atorvastatin
| simvastatin
412
What do statins do
How is this useful
inhibit HMG-CoA reductase
increases circulating LDL uptake by the liver so blood LDL levels drop, and risk of atheroma formation drops
413
What enzyme is responisble for the rate limiting step in cholesterol synthesis
HMG-CoA reductase
| hydroxymethylglutaryl-coenzyme A reductase
414
What happens in HMG-CoA is blocked
liver has to take up more LDL from the blood (to keep the
| cholesterol pool for the enterohepatic circulation topped-up)
415
How does the liver take up more LDL from the blood when statins are taken
synthesising new LDL receptors
416
Who are statins prescribed for currently
people who either already have
| ischaemic heart disease, or who are in ‘high risk’ groups (normally based on family history)
417
What is SRE
Where is it found
What is its job?
sterol response element
in the LDL receptor gene promoter
monitors presence of sterols in the cell and reguates LDLD receptor transcription
418
Does the SRE up or down regulate LDL receptor expression
up OR down according to cellular sterol levels
419
What are the 2 key molecules that interact with SRE
SRE-binding proteins 1 and 2 (SREBP-1 and -2).
420
Describe the structure and normal location of SREBPs
contain two transmembrane domains
| and are normally anchored in the ER
421
How are the SREBPs taken to the Golgi from the ER
```
SREBP cleavage
activating protein (SCAP) acts as a chaperone protein and it transports the precursor SREBPs to the Golgi.
```
422
What happens to the SREBPs in the Golgi
What is important to remember about this reaction
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
What happens after the 2 halves of SREBP have separated
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
How does the overall benefit of statins compare to what it should be theoretically
What does this suggest
benefits are greater than that which might be expected
from changes in lipid levels alone.
effects independent of cholesterol-lowering
might occur
425
What are other benefits of the pleiotropic effects of statins (5)
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
How do the brains of people who took statins differ from those who did not
The statin-treated group showed
| significantly fewer pathological features of Alzheimer’s disease
427
Why do we want alternatives to statins
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
What are recently introduced drugs that are statin alternatives
PCSK9 Inhibitors
429
What is PCSK9
(proprotein convertase subtilisin/kexin type 9 - is a circulating enzyme, produced by the liver, that is involved in LDL receptor turnover.
430
What happens when PCSK9 interacts with the LDL receptor
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
What are Evolocumab and alirocumab
What do they lead to
how must they be administered
monoclonal antibodies, that target and inhibit PCSK9
enhance the internalisation and recycling of LDL receptors (and hence uptake of LDL)
injection
432
Name 2 PCSK9 inhibitors
Evolocumab
| alirocumab
433
Name a fibric acid derivative which lowers VLDL and LDL
bezafibrate
434
What does bezafibrate do
How does this help
What molecule does the action action rely upon
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
How does HDL provide protection from ischaemic vascular disease
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
How is cholestrol transferred to the HDL from non-hepatic tissue
What is it transferred to in the first step of the mechanism
by the ATP-binding cassette transporter ABCA1
simply to ApoA-1 as
a first stage in building-up the lipoprotein
437
What does Apo-A act as in reverse cholesterol transport
What is the role of the rest of the HDL molecule
acts as an acceptor
the phospholipid component of HDL acts as a sink for the mobilised
cholesterol.
438
What happens to the cholesterol to prepare it for transport in the HDL
converted to cholesteryl esters by the
| action of the enzyme lecithin cholesterol acyltransferase (LCAT).
439
What can cholesteryl esters be transferred to
However, what mediates most of the liver's uptake of cholesteryl esters from HDL
other lipoproteins (including LDL) that can be taken up by the liver by the LDL receptor
the receptor SR-B1 (‘Scavenger Receptor B1)
440
What is SR-B1
Where is it found and what can it do
Scavenger Receptor B1
present on liver cells’ PMs
mediates most of the liver’s uptake of cholesteryl esters from HDL
441
What happens when the cholesteryl esters from HDL in the liver
converted to cholesterol and enter the general pool.
442
What is the rate limiting step of HDL formation
removal of cellular phospholipids and cholesterol by apoproteins or by lipid-poor HDL from peripheral cells and tissues.
443
What is Tangier disease
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
What did a study of people with Tangier disease show
that ABCA1 controls the rate-limiting step in cellular phospholipid and cholesterol efflux.
445
How is expression of ABCA1 controlled
d by the cell’s content of cholesterol via activation
| of ‘liver X receptors’ (LXRs
446
What do LXRs act as
metabolic sensors for cholesterol content of cells, allowing
| the organism to quickly adapt to increases in cholesterol levels.
447
What induces LXR transcription in cells
what does this lead to
The nuclear receptors, peroxisome
proliferator-activated receptor (PPAR)alpha and PPARgamma
increased LXR alpha transcription induces ABCA1 expression
448
Name a PPAR gamma agonist
pioglitazone
449
What is pioglitazone used to treat
T2 diabetes
also reported to reduce atherosclerosis
450
How do fibrate drugs work overall
activating PPARs
451
Name 2 agents that are involved in enterohepatic circulation (not fibrate drugs)
Colestyramine
Ezetimibe
452
What is colestyramine
what does it do
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
What does ezetimibe do
Is it usually used alone?
inhibits the intestinal absorption of cholesterol.
can be used in combination with a statin or alone
454
What is the molecular target of ezetimibe
‘Niemann-Pick C1-Like 1' (NPC1L1)
455
What is ‘Niemann-Pick C1-Like 1' (NPC1L1) named after
| this is just a foot note so not as important
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
What does NPC1L1 do
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
Why can ezetimibe be reused by the body over and over again
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
How does nicotinic acid affect blood LDL (3)
inhibits liver triglyceride production and VLDL secretion when used in very large doses.
It increases levels of t-PA
459
What are the effects of fish oil
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
How does the increased amounts of highly unsaturated fatty acids
in fish oil reduces risk of thrombosis
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
What is the etymology of angina
gina
The term ‘angina pectoris’ comes from the two Latin words angere and pectus (meaning
strangle and chest respectively).
462
What is angina
severe, suffocating chest pain
463
Where can angina pain be referred to
left shoulder and upper arm and sometimes the teeth
464
What is variant angina
What provokes it
How does it compare to regular angina
‘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
why is the coronary circulation unusual
during
systole, the myocardium receives little blood (and so oxygen) supply, but blood does perfuse the
myocardium during diastole
466
Why is the myocardium only supplied with blood during diastole
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
What kind of innervation tends to predispose angina patients with pain
Why (3)
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
Why is SNS stimulation on the heart not a problem for non-angina patients
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
How do angina patients' bodies compensate for the decreased blood flow
angiogenesis: they develop collateral blood vessels
470
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
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
Can a normal person develop collateral blood vessels?
yes, develop in normal individuals who take regular, sustained aerobic exercise.
472
Why is the term nitrovasodilators a misnomer
all of these drugs are in fact organic
| nitro derivatives
473
Name 3 nitrovasodilators
When are each used?
glyceryl trinitrate
isosorbide mononitrate
amyl nitrite
first 2 in angina (glyceryl trinitrate especially in acute attacks)
amyl nitrate is a recreational drug (Poppers)
474
How is glyceryl trinitrate taken
why
sublingually
s poorly absorbed from the stomach
and so it is taken sublingually (where it is absorbed directly into the systemic circulation)
475
What is required to happen to isosorbide dinitrate for it to work
metabolised in the liver to isosorbide mononitrate
476
How do nitrovasodilators cause vasodilation
by being converted to
nitric oxide (NO) in vascular smooth muscle cells by endothelial cell Ca2+
-sensitive nitric oxide synthase - ecNOS
477
What is glyceryl trinitrate also used in
This is actually nitroglycerin, the major component of dynamite
478
What is the main way nitrovasodilators work in angina patients
venous dilation
| can also cause collateral vasodilation
remember coronary arteries cannot dilate more
479
Why does nitrovasodilators causing venous dilation help with angina
reduced central venous pressure, the right atrial filling pressure and
thus the work done by the heart (Starling’s Law)
480
what is the fortuitous feature of the action of nitrovasodilators
they produce vasodilatation in collateral vessels in ischaemic areas, while not affecting dilatation in well oxygenated areas
481
What is coronary steal
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
What drug causes coronary steak
vasodilator drugs, such as dipyridamole (which stimulates adenosine
receptors)
483
What can be a secondary response to use of nitrates to alleviate angina?
A severe headache
Changes in cerebral blood flow can cause severe headaches. This partly explains what happens in migraine.
484
Name 2 ß1
| antagonist
bisoprolol and atenolol
485
How are ß1
| antagonist useful in angina
decrease SNS stimulation on heart
decrease blood pressure to decrease afterload (reducing work done by the heart)
486
why are non specific beta antagonists less useful in angina
```
unwanted effects:
eg bronchoconstriction
coronary vasoconstriction (alpha 1 mediated)
```
487
Why do non specific beta blockers result in coronary vasoconstriction
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
Why might it be dangerous to completely block the SNS with beta blockers in an angina patient
In heart failure (which
frequently occurs concurrently with angina) it is necessary to maintain sympathetic stimulation to
produce an adequate cardiac output
489
How do dihydropyridine channel blockers act
t by blocking Ca2+
entry into vascular smooth
muscle cells, causing vasodilation, reduced BP and reduced afterload
490
What is the most commonly used dihydropyridines Ca2+ channel antagonists
amlodipine
491
why do dihydropyridines work on
vascular smooth muscle in preference to cardiac Ca
2+ channels?
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
Name a If blocker
Which protein does it actually block
ivabradine
HCN channel
493
Where is the If current highly expressed in the heart
What is the effect of blocking it
SAN
reduces cardiac pacemaker activity, slows the heart rate and allows more time for blood to
flow to the myocardium
494
Why does ivabradine often help angina patients (other than allowing more time for blood to perfuse the myocardium)
people with stable angina often have very high heart rates, so ivabradine may help these individuals.
495
Why does ivabradine not affect cardiac conduction, myocardial contractility or ventricular repolarisation.
acts on the HCN channel which is primarily in the SAN so the drug is selective to SAN
496
What is a benefit of ivabradine over beta blockers in angina
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
Is ivabradine a popular drug?
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
What part of the heart does ivabradine act on
solely the SAN (not really AVN etc )
499
What is the main mode of action of ranolazine
to inhibit the late phase of the sodium current in cardiac myocytes
(can act on other parts of the cardiac AP)
500
What does the late Na current in the ischaemic myocardium AP result in
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
What is the problem of Ca2+ overload in ischaemic cardiomyocytes following the late inward Na current
impairs relaxation, increasing ventricular diastolic wall stiffness and end-diastolic pressure, hence worsening ischaemia
502
How does increased ventricular diastolic wall stiffness and end diastolic pressure result in increased ischaemia
stiffness causes mechanical
compression of the microcirculation within the wall of the ventricles, which impairs coronary blood
flow during diastole and worsens ischaemia
503
How does ranolazine improve angina
Blocking late inward Na current means Ca2+ overload and diastolic wall
stress are reduced, leading to improved coronary blood flow and decreasing ischemia
504
How is the degree of tissue damage following MI as a result of the initial ischaemic event determined
primarily determined by its duration, and then subsequent injury resulting from reperfusion.
505
How can you improve the heart's ability to withstand longer periods of ischaemia
ischaemic preconditioning
506
What is ischaemic preconditioning
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
How can we use ischaemic preconditioning clinically
What is it used to treat
can be stimulated (it
| seems) by use of the K(ATP)-opening drug, nicorandil, which can be used in angina
508
What is the MPTP
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
What does the MPTP do when the heart is reperfused after an ischaemic episode
opens (after remaining closed during the ischaemia)
510
Name 4 things which can cause the MPTP to open
What is common about these 4 things
high mitochondrial [Ca2+], oxidative stress, ATP depletion and mitochondrial depolarisation,
all present during reperfusion.
511
What does opening of the MPTP during reperfusion result in
What does this in turn lead to
```
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
What is responsible for the rise in mitochondrial ROS after ischaemia
accumulation of succinate (an intermediate of the citric acid
cycle) builds up during ischaemia
513
What is the end effector of ischaemic preconditioning
A mitochondrial ATP-sensitive potassium channel (mitoK(ATP))
514
How can opening of the mitoK (ATP) channel protect the myocardium after ischaemia
What provides evidence for this hypothesis
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
Why is energy state improved by opening of the mitoK(ATP) channel
decreases F1 Fo
-ATPase, which is the main consumer of ATP in ischaemia
(ATP synthase in reverse)
516
Is the role of nicorandil solely as the mitoK(ATP) channel opener
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
How does nicorandil's role as a nitric oxide donor help in preconditioning
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
How can preconditioning be blocked and mimicked
by antagonists at adenosine receptors
can be mimicked by adenosine A1
receptor agonists
519
How do interstitial [adenosine] change in ischaemia
What are the effects of this (3)
increase
adenosine has negative inotropic and chronotropic actions (to reduce cardiac oxygen demand).
also inhibits activation of neutrophils.
520
What is revascularisation used to do
How can it be achieved
either to improve prognosis or symptoms
by either
coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
521
How was angioplasty achieved in the early 80s
What were the issues with this (2)
Give technical names of both
balloon dilation
re-narrowing of the vessel (‘restenosis’)
development of scar tissue that
encroached into the lumen (neointimal proliferation)
522
What was the refinemetn made to the PCI technique introduced in the mid-1980s
How was this an improvement
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
What was the problem of stents in the late 1980s
How is this overcome
did not prevent neointimal proliferation (actually increased it)
‘drug-eluting stents’. They are coated
with a polymer within which are embedded antiproliferative drugs
524
How common is restenosis in patients who have drug eluting stents
down to only 5-10% of cases
525
WHat are the 2 types of antiproliferative drug eluting stents
The first elutes sirolimus
The second elutes
paclitaxel (also called ‘Taxol’) which interferes with the normal function of microtubule growth
526
What is sirolimus commonly used as (other than in drug eluting stents)
as an immunosuppressant drug.
527
What is Taxol used in other than in drug eluting stents
Paclitaxel/Taxol is used as an anticancer drug.
528
How are antidysrhythmic agents classified
by the Vaughn Williams classification (I-IV)
529
What are class I antidysrhythmic drugs
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
What are class IA antidysrhythmic drugs
2 examples
block VG Na channels
Increased action potential duration, with an intermediate rate of association/ dissociation.
quinidine and procainamide
531
What are IB antidysrhythmic drugs
eg
block VG Na channels
Decreased action potential duration, with very fast association and dissociation. Example:
lidocaine
532
What are IC drugs
eg
anti dysrhythmic drugs that block VG channels
No effect on action potential duration, but very slow association and dissociation.
Example: flecainide
533
What are class II antidysrhythmics
Sympathetic antagonists (i.e. ß-blockers). Examples: propranolol, atenolol
534
What are class III antidysrhythmics
these drugs prolong the action potential and thus also the refractory period. The best known
example is amiodarone
535
What are class IV antidysrhythmics
These are Ca2+-channel blockers which reduce thus Ca2+ entry. The most commonly used is
verapamil
536
What are class I antidysrhythmic agents useful for
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
Describe the affinity of Class IA antidysrhythmic drugs
what does this mean
What are they used to treat
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
Which antidysrhythmic drugs show use dependence
```
class IA
class III
```
539
describe the affinity of class IB antidysrhythmic drugs
What does this mean
have greater affinity for the inactivated
than the activated states.
therefore influenced by length of AP
540
How does the rate of dissociation of class IB antidysrhythmic drugs change
why
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
When are IB antidysrhythmic drugs most effective
* 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
Describe association and dissociation of class IC drugs
What does this mean they are good at
what does it also mean
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
What are Class II antidysrhythmic agents - general effect?
ß1 antagonists (ß-blockers) and so decrease the effects of catecholamines on
the heart
(negative inotropic and chronotropic effects)
544
When are Class II antidysrhythmic agents used
eg
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
what drugs can be used in dysrhythmias where the tissue abnormality leads to increased excitability
ß1
antagonists (ß-blockers)
cardiac glycosides
546
Can some antidysrhythmic drugs fit into >1 category
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
Name a Class III antidysrhythmic agents
amiodarone
548
What do Class III antidysrhythmic agents do
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
Does amiodarone inhibit inward or outward currents
both
550
How is amiodarone inhibition of inward Na+ and Ca2+ currents enhanced
What is the result
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
The inhibition of inward Na and Ca currents by amiodarone is greater in which tissues
in the tissues stimulated at higher frequencies and in those with less negative
resting membrane potential
552
Which outward K+ channels are inhibited by amiodarone
depends on amount of amiodarone present
553
When would amiodarone cause shortening of AP duration
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
What are Class IV antidysrhythmic agents
Name one
These are Ca2+-channel antagonists that are selective for the myocardium
verapamil
555
verapamil is an example of which drug
Class IV antidysrhythmic agent
| These are Ca2+-channel antagonists
556
Why are Class IV antidysrhythmic agents useful for many kinds of dysrhythmia
Ca2+
| channels are ubiquitous in the heart
557
Why must Class IV antidysrhythmic agents not be taken excessively
Ca2+ entry is important for producing the excitation-contraction coupling in cardiac muscle so excess may inhibit contraction
558
Why arent class IV anti dysrhythmic drugs given when cardiac function is severely compromised
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
Are all Ca2+ channel blockers useful as antidysrhythmic agents
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
How does verapamil affect myocardial oxygen demand
the slowing of the heart it also produces will also decrease oxygen demand
561
How do ß-blockers affect myocardial Ca2+ influx
decrease Ca influx
562
Name 2 drug types that do not fit into the Vaughn Williams classification but can be used for angina
adenosine
| cardiac glycosides
563
What is the mechanism of action of adenosine in dysrhythmia
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
Which dysrhythmias can adenosine be used to treat
What is an advantage of it in these circumstances
for certain
supraventricular tachycardias
its short half-life can have some advantages
565
How do cardiac glycosides act to treat angina (3)
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
Which drugs in the Vaughn Williams classification are pro-dysrhythmic
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
