Cardiovascular Pharmacology (Concepts) Flashcards

1
Q

What is the structure of Navs?

A
  • Contains 3 subunits:
    1. α: Forms pore
    2. β12: Modifies current
  • α subunit contains 4 domains each with 6 transmembrane loops (S1-S6)
  • Pore region formed by S5 and S6
  • Selectivity filter is provided by S6
  • S4 in each domain contains large proportion of +ve amino acids and acts as voltage sensor
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2
Q

What are the regions in Navs responsible for inactivation?

A
  • Cytoplasmic loop between domains III and IV.
  • S6 in domain IV.
  • Linking region between S5 & S6 in domain IV.
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3
Q

Where do local anaesthetics act on Navs?

A

C-terminus of the Nav located intracellularly

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4
Q

What is the structure of Cavs?

A
  • Cavs are made up of 5 subunits (α1, α2, β, γ, δ).
  • α1 forms the pore while other subunits are accessory subunits with various functions/
  • α2 and δ subunits are linked by disulfide bridge and are products of same gene
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5
Q

In which tissue to γ subunits of Cavs occur?

A

Skeletal muscles

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6
Q

What are the functions of β and α2δ subunits in Cavs?

A
  1. Modifying current
  2. Influencing intracellular tracking of channel
  3. Influencing channel trafficing to PM
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7
Q

What are the different drugs that act on the Cavs?

A
  • Dihydropyridines (e.g. Nifedipine)
  • Phenylalkylamines (e.g. Verapamil)
  • Benzothiazepines (e.g. Diltiazem)
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8
Q

What are the sites of action of phenylalkylamines?

A

42 amino acid region making up S5/S6 linking region and S6 in domain IV.

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9
Q

What are the sites of action of dihydropyridines?

A

2 binding sites:

  1. S6 and S5/S6 linking region in domain III.
  2. S5/S6 linking region in domain IV.
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10
Q

What are the sites of action of benzothiazepines?

A

S6 in domain IV.

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11
Q

What is the method used to elucidate binding sites of drugs on receptor?

A
  • Photoaffinity labelling:
    1. Radiolabelled version of ligand in question is linked with photoreactive group.
    2. Photoreactive group forms covalent bond with receptor upon light exposure.
    3. Receptor-ligand complex cleaved in order to determine site of covalent bond and region of ligand interaction.
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12
Q

What are the types of Cavs?

A
  • T-type
  • L-type
  • N-type
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13
Q

What are the properties of T-type Cavs?

A
  • Mainly present in pacemaker region
  • Small depolarisation needed to open (10-20 mV)
  • Open transiently (short time)
  • Small current produced (~8 pS)
  • Not sensitive to dihydropyridines
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14
Q

What does the T in T-type stand for?

A
  1. Tiny depolarisation needed to open
  2. Tiny single channel conductance
  3. Transient opening
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15
Q

What is the functions of T-type Cavs in the heart?

A

Opening may depolarise cardiac tissue enough for threshold to be reached and AP to be triggered

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16
Q

What are the properties of L-type Cavs?

A
  • Large depolarisation needed to open (~30 mV)
  • Open for extended period of time upon activation
  • Produces large current (9-27 pS)
  • Activity enhanced by NA and Adr through phosphorylation
  • Sensitive to dihydropyridines
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17
Q

What does the L in L-type stand for?

A
  • Long time opening
  • Large depolarisation needed to open
  • Large single channel conductance
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18
Q

What is the function of L-type Cavs in the heart?

A

Responsible for plateau phase in cardiac AP and is main source of depolarising current in pacemaker tissue

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19
Q

What are the functions of K+ channels in the heart?

A
  • Repolarisation
  • Stabilisation of resting potential
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20
Q

What are the properties of N-type Cavs?

A

Found in pre-synaptic terminal of neurones and mediates depolarisation-dependent exocytosis.

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21
Q

What is the structure of Kvs?

A
  • Made up of 4 separate proteins, each containing 6 transmembrane loops.
  • S4 is the voltage sensor.
  • S5 and S6 form the pore and selectivity filter.
  • Ball and chain domain at N-terminus of each subunit involved in activation.
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22
Q

What are the types of Kv inactivation?

A
  • N-type: Ball and chain domain on the N-terminus of either subunit swings into the pore to block it.
  • C-type: Movement of residues on the extracellular mouth of pore. Could be dilation of mouth to prevent dehydrating interactions with K+ ions and thus inactivation.
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23
Q

What is the main function of inward-rectifying K+ channels in cardiac cells?

A

Decreases K+ loss from cardiac cells as a consequence of constant depolarisation.

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24
Q

What mechanisms are responsible for the inward-rectifying properties of Kirs?

A
  1. Mg2+
  2. Intracellular polyamines (e.g. spermine)
25
Q

What are the other functions of Kirs in cardiac tissue in addition to mediating IK1?

A
  1. IK-ACh: Mediated by GIRK channels and partially responsible for parasympathetic effects on the heart.
  2. IK-ATP:
    - When O2 supply is low, intracellular [ATP] also decreases.
    - This opens KATP channels and hyperpolarises the cells, reducing their contractility and subsequent O2 consumption.
26
Q

What are the phases of the cardiac action potential?

A
  • Phase 0: Rapid depolarisation due to opening of voltage-gated Na+ channels once the membrane has depolarised above threshold.
  • Phase 1: Inactivation of Na+ channels and the slow activation of Ca2+ channels means that there is a brief period of repolarisation where the outward K+ channel dominates.
  • Phase 2: Opening of Ca2+ channels counteract the outward K+ current and holds membrane at depolarised potential. This is the plateau phase.
  • Phase 3: The membrane repolarises as more slow-activating K+ channels open and the outward current dominates the inward current.
  • Phase 4: Membrane returns to resting potential of around -90mV (electrical diastole).
27
Q

Which ion channels are responsible for the various parts of the cardiac AP?

A
28
Q

What is long QT syndrome caused by?

A

LQT1/2: Kv mutation (43%/45%)

LQT3: Nav mutation (7%)

29
Q

What are the symptoms of long QT syndrome?

A
  • Transient loss of consciousness (syncopy)
  • Ventricular dysrhythmias
  • Sudden Adult Death Syndrome (SADS) (ventrcular fibrillation)
30
Q

What types of drugs are used to treat long QT syndrome?

A

β1-adrenorecepotr antagonists (prophylaxis)

31
Q

What are other causes of SADS?

A

Hypertrophic/dilated cardiomyopathies

32
Q

What is the mechanism of self-depolarisation at the SAN?

A
  1. At rest, there is an inward depolarising current from pacemaker cells. This is called the funny current (If).
  2. The If depolarises the membrane to beyond threshold, which causes voltage-gated Ca2+ channels to open.
  3. This results in depolarisation and the disappearance of If.
  4. K+ channels open and SAN cells repolarise.
  5. Once the membrane repolarises to resting potential, If reappears to depolarise cell to threshold and retrigger APs.
33
Q

What are the differences between the SAN AP and regular atrial/ventricular AP?

A
  1. Spontaneous depolarisation due to presence of If
  2. Depolarisation mediated by L- and T-type Cavs as Navs are absent
34
Q

What are the effects of sympathetic stimulation on the heart?

A
  • Increased heart rate
  • Increased contractility
  • Increased automaticity
35
Q

What is the sequence of events during sympathetic stimulation?

A
  1. Noradrenaline binds to β1 receptors on cardiac myocytes.
  2. This activates associated Gα-protein, which activates adenylyl cyclase.
  3. Adenylyl cyclase synthesises cAMP, which in turn activates PKA.
  4. PKA phosphorylates a number of different proteins that cause the effects of sympathetic stimulation.
36
Q

How does sympathetic stimulation increase heart rate?

A
  1. PKA phosphorylates L-type Ca2+ channels and increases their probability of opening. This increases rate of nodal cell depolarisation.
  2. cAMP binds directly to C-terminus of HCNs and promote their activity. This increases voltage at which If is activated and so If activated sooner after repolarisation.
  3. Increased pacemaker current causes increased rate of spontaneous depolarisation, leading to increased heart rate.
  4. Enhanced activity of delayed-rectifying K+ channels, which increases rate ioff repolarisation and reduces length of AP.
37
Q

What are the effects of increased delayed-rectifying K+ channel activity?

A
  • Decreased duration of cardiac AP and thus increased heart rate.
  • Increased time spent in diastole and increased filling time, leading to increased CO.
38
Q

How does sympathetic stimulation increase heart contractility?

A
  1. PKA phosphorylates L-type Ca2+ channels (possibly through α1 subunit) and increases their probability of opening. This increases Ca2+ entry into cell during AP and increases CICR from ER, thus increasing strength of contraction.
  2. PKA phosphorylates SERCA2, which may result in more Ca2+ sequestration and thus greater Ca2+ release, resulting in greater strength of contraction.
  3. PKA may also phosphorylate troponin C, which increases its sensitivity to Ca2+.
  4. Sensitisation of ryanodine receptors in SR of cardiac myocytes, increasing amount of Ca2+ released by CICR.
39
Q

What are the negative side-effects of sympathetic stimulation on the heart?

A
  • Reduced efficiency (O2 consumption increases without proportional increase in work)
  • Cardiac hypertrophy
40
Q

What is the sequence of events during parasymapthetic stimulation of the heart?

A
  1. ACh binds to M2 receptors in the nodal tissue and atrial myocardium.
  2. This stimulates Gi-proteins whose αi subunits inhibit adenylyl cyclase and causes decrease in [cAMP].
  3. βγ subunit directly activates GIRK K+ channels in the nodal tissue.
41
Q

How does parasympathetic stimulation decrease heart rate?

A
  1. Decreased levels of cAMP causes decrease in activity of PKA and reduced levels of phosphorylation of L-type Cavs, decreasing probability of opening in nodal tissue, thus reducing rate of depolarisation.
  2. Decreased levels of cAMP shifts voltage at which HCNs activate to more negative values.
  3. Activation of GIRK causes increased outward K+ current (IK-ACh) , causing hyperpolarisation of nodal tissue, meaning that it takes longer for If to depolarise tissue to AP firing threshold.
42
Q

What are the 3 major causes of dysrhythmias?

A
  1. Damage/dysfunction to SAN
  2. Damage to myocardium
  3. Damage/dysfunction of conductive pathway
43
Q

What are the discharge rates of the different cardiac elf-excitable tissues under normal conditions?

A

SAN: 70 min-1

AVN: 60 min-1

Bundle of His: 50 min-1

Purkinje fibres: 40 min-1

44
Q

How can damage to the SAN as a cause dysrhythmias to arise?

A
  • If AVN takes over, heart-rate will be slower than normal and the atria would not contract, potentially decreasing CO by up to 30%.
  • If ectopic pacemakers arise, they may cause dysrhythmias such as ectopic tachycardias.
45
Q

How can damage to the myocardial tissue cause dysrhythmias?

A
  • Under normal circumstances, cardiac action potentials collide at specific points in space on the myocardium. Because each AP is followed by an inexcitability gap, they cancel each other and so the APs are extinguished.
  • When tissue damage occurs on the other hand, these APs may be slowed down at certain points or blocked all together, which alters timings of these impulses so that they don’t meet each other at specific points and extinguish each other. Instead, they are able to circulate around cardiac tissue, causing re-entrant arrhythmias.
46
Q

What is Wolff-Parkinson-White syndrome?

A

Accessory conduction pathway between atria and ventricles bypassing AVN results in abnormally quick conduction of cardiac impulses from atria to ventricles, resulting in supraventricular tachycardias.

47
Q

What is heart failure?

A

Heart fails to maintain cardiac output adequate to meet the metabolic demands of the body.

48
Q

What are examples of causes of chronic heart failure?

A
  • Myocardial infarction
  • Dysrhythmias
  • Hypertension
  • Heart valve defects
  • Heart muscle diseases (e.g. cardiomyopathies, inflammation)
  • Congenital heart defects
  • Lung disease
  • Hyperthyroidism
49
Q

What are the New York Heart Association classifications for heart failure?

A
  • Class 1: Minimal dyspnoea
  • Class 2: Dyspnoea while walking on flat land
  • Class 3: Dyspnoea while getting in/out of bed
  • Class 4: Dyspnoea while laying in bed
50
Q

What is the mechanism of action of cardiac glycosides in treating heart failure?

A
  • They inhibit action of Na+/K+-ATPase in cardiac myocytes.
  • This causes dissipation of the Na+ gradient across cardiac myocyte PM and decreased efficiency of NCX.
  • Less Ca2+ pumped out of myocytes between contractions result in more being sequestered into SR by SERCA.
  • More Ca2+ released in subsequent contractions result in stronger contractions and increased cardiac function.
  • Cardiac glycosides only lower intracellular Na+ by 1-1.5mM. However, this has significant effect in intracellular Ca2+ as it is inversely proportional to [Na+]3.
51
Q

Why are cardiac glycosides rarely used for heart failure now?

A

They have strong dysrhythmic effects.

52
Q

What is the mechanism of action of β1 agonists in treating heart failure?

A

Stimulation of the heart via β1 receptors mimics sympathetic stimulation, increasing heart rate and contractility, thus increasing cardiac output.

53
Q

What are the disadvantages of β1 agonists as treatment for heart failure?

A
  • Decreases efficiency of heart, so increases O2 demand on already possibly ischaemic myocardium, further degrading its condition.
  • Has strong dysrhythmic effects.
  • Increases MAP and may result in hypertension.
54
Q

What is the role of β1 agonists in treating heart failure?

A

Dobutamine is only one used and only used intravenously to treat shock due to its quick effects.

55
Q

What is the mechanism of action of β blockers in treating heart failure?

A
  • During heart failure, there is a decrease in MAP as a result of decreased CO, which results in reflex increase in sympathetic stimulation of the heart.
  • Chronic stimulation of heart by noradrenaline may promote apoptosis of cardiac myocytes.
  • β-blockers prevent this from happening and act as a conservative treatment; not improving cardiac function but preventing any further degeneration.
56
Q

What is the mechanism of action of inodilators?

A
  • Phosophodiesterase inhibitors that inhibit cAMP breakdown, increasing intracellular [cAMP].
  • It has an inotropic effect as it increases [cAMP] in cardiac tissue, mimicing sympathetic stimulation.
  • It has a dilator effect as it increases [cAMP] in VSM, leading to vasodilation and decreased after-load on heart and thus stress.
57
Q

What is the mechanism of action of methylxanthines?

A
  • Inhibit phosphodiesterase activity and A1/2 receptor activity (Adenosine receptors).
  • Increase strength of contraction through same mechanisms as inodilators.
  • Additional inotropic effects mediated through Ca2+ release due to A1/2 inhibition.
  • May have dysrhythmic effects.
58
Q

What is the mechanism of action of Ca2+ sensitisers?

A
  • Increases binding efficiency of Ca2+ to cardiac troponin C, increasing strength of contraction with minimal increase in energy consumption.
  • Inhibits phosphodiesterase III in VSM and causes vasodilation via same mechanism as inodilators.
59
Q

What is the gold standard for treating heart failure?

A

ACE inhibitors combined with β blockers