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Year 2 - LCRS - Pharmacology > Drugs and the Cardiovascular System: The Heart > Flashcards

Drugs and the Cardiovascular System: The Heart Flashcards

1
Q

Describe what occurs during an AP in the heart.

A
  • cells in the SA node are the pacemaker of the heart, they generate spontaneous APs
  • Funny channels (If) switch on during hyperpolarised states, use cAMP (on their own they are not enough to cause depolarisation, but they start the process) - (hyperpolarization-activated cyclic nucleotide–gated (HCN) channels)
  • transient calcium channels open (ICa(t))
  • long lasting calcium channels open (ICa(l))
  • the calcium influx is what causes the depolarisation and drives HR
  • IK current: Potassium channels initiate depolarisation

The entire process is spontaneous, there is no specific stimulus that causes depolarisation however it can be influenced by PNS and SNS actions

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2
Q

What is different about the cardiac AP?

A
  • the depolarizing current is carried into the cell primarily by relatively slow Ca++ currents instead of by fast Na+ currents. There are, in fact, no fast Na+ channels and currents operating in SA nodal cells.
  • the cells in the heart have no true resting potential
  • cells in the SA node are the pacemaker of the heart, they generate SPONTANEOUS APs (there is no particular stimulus that drives depolarisation but it is influenced by SNS and PNS
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3
Q

If current

A
  • hyperpolarization-activated cyclic nucleotide–gated (HCN) channels
  • require cAMP
  • cause depolarisation in a hyper polarised state, but not enough depolarisation for an AP
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4
Q

What are the cellular effects of the PNS and SNS on HR?

A 
SNS:
- increased cAMP
- increased If current (depo initiation)
- increased Ica current (demo)
=> increased HR

PNS:
- decreased cAMP
- increased IK current (repo)
=> decreased HR

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5
Q

What are the mechanisms that control contractility?

A
  1. AP from adjacent cell (down t-tubule)
  2. VGCC opens and Ca2+ enters the cell
  3. Ca2+ induces Ca2+ release (CICR) through Rhyanodine receptor channels (RyR channels)
  4. local release causes Ca2+ spark
  5. summed Ca2+ sparks create Ca2+ signal
  6. Ca2+ ions bind to troponin to initiate contraction
  7. relaxation occurs when Ca2+ unbinds from troponin
  8. Ca2+ is pumped back into the SR for storage
  9. Ca2+ is exchanged for Na+
  10. Na+ gradient is maintained by Na+/K+-ATPase
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6
Q

What are the sources of Ca2+ in cardiac cells during contraction?

A
  • Depolarization-induced influx of Ca2+ current (ICa) through the L-type channels contributes approximately 20–25% of the free Ca2+ in a cardiac twitch.
  • The release of Ca2+ through the RyRs contributes the remaining 75–80% of Ca2+ necessary for cardiac contraction.

=> 75% from SR, 25% from outside (ec)

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7
Q

What are the mechanisms regulating myocardial oxygen supply and demand?

A

Oxygen Supply:

  • increased Coronary blood flow
  • increased Arterial O2 content

Oxygen Demand:

  • increased HR (more contractions)
  • increased preload (small increase in FOC, 25% in 100& volume increase; increases work of heart due to starlings law, linked to SV)
  • increased afterload (the more resistance there is the harder the heart has to work to pump blood through the system -> greater FOC)
  • increased contractility (greater FOC)

Myocyte contraction = primary determinant of myocardial oxygen demand

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8
Q

Name the main drugs influencing HR and their mechanism to do so.

A
  • beta-blockers (decrease If and ICa; inhibits the SNS from increasing HR, especially if you have a beta-1-selective blocker)
  • calcium antagonists (decrease ICa)
  • Ivabradine (decrease If and speed of depolarisation)
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9
Q

Which Ca2+ channels do CCBs block?

A

L-type

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10
Q

How do beta blockers decrease HR?

A
  • beta adrenoceptors are the predominant receptors on the heart
  • the SNS increases nodal activity by increasing cAMP which increases If as well as by having a positive effect on Calcium influx
  • if these actions are blocked by a beta blocker (beta-1-selective in particular) the heart will beat slower
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11
Q

How do Calcium antagonists/CCBs decrease HR?

A
  • Ca2+ is the predominant ion driving HR

- if you decrease the amount of Ca2+ you will slow the heart down

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12
Q

How does ivabradine decrease HR?

A
  • blocks the If current

- if you block this current you decrease the depolarisation speed by creating more space between depolarisations

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13
Q

Name the drugs that influence contractility of the heart.

A
  • beta-blockers
  • Calcium antagonists
  • organic nitrates
  • potassium channel openers
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14
Q

How do beta-blockers decrease contractility?

A
  • contractility is SNS driven
  • b1 is important for calcium entry
  • if you block the beta-1-R you
  • ability to initiate contraction is impaired
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15
Q

How do CCBs decrease contractility?

A
  • if you directly decrease the inward calcium current you decrease contractile force
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16
Q

What are the 2 classes of CCBs?

A
  • rate slowing

- non-rate slowing

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17
Q

Name examples of rate-slowing CCBs. When would you use them?

A
  • (Cardiac and smooth muscle actions; slow HR and decrease contractility)
  • Phenylalkylamines (e.g. Verapamil)
  • Benzothiazepines (e.g. Diltiazem)
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18
Q

Name examples of non-rate-slowing CCBs. When would you use them?

A
  • (smooth muscle actions – more potent; cause vasodilation; great in vasculature, not much action in the heart)
  • Dihydropyridines (e.g. amlodipine)

-> No effect on the heart. Profound vasodilation can lead to reflex tachycardia

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19
Q

How does NO work?

A
  • it increases cGMP (via positive actions on sGC (soluble guanylate cyclase) which causes
    a) relaxation and (directly)
    b) opening of potassium channels which in turn causes hyper polarisation and makes contraction more difficult to initiate) -> making it more difficult to contract
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20
Q

How do potassium channel openers work?

A
  • cause K+ efflux
  • this causes hyperpolarisation
  • this makes it more difficult for the cell to contract
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21
Q

What are the effects of organic nitrates and potassium channel openers on coronary BF?

A

increase CBF

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22
Q

What are the effects of organic nitrates and potassium channel openers on preload and after load?

A
  • decrease preload due to venodilation
  • decrease afterload due to vasodilation

=> their effects are not only on the heart but also on Bis

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23
Q

Summary of drugs acting on the heart in angina

A
  • CCB: decreases contractility and HR
  • Beta-blockers: decreases contractility and HR
  • Ivabradine: decreases HR
  • nitrates: improves coronary BF via vasodilation (relaxation and hyperpolarisation), decreases preload and afterload
  • K+ channels openers: improve coronary BF via vasodilation (hyperpolarisation)
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24
Q

What is stable angina?

A
  • e.g. only during exercise or in the presence of exacerbating factors
  • predictable
25
Q

What are the guidelines in treating stable angina?

A
  • 1st line: CCB or BB (decide based on comorbidities, contraindications and the patients preferences)
  • if not tolerated, consider switching CCB and BB
  • if unsatisfactory control of symptoms either switch CCB and BB or use in combination
  • if the person cannot tolerate CCB and BB or they are contraindicated give:
    a) a long acting nitrate OR
    b) ivabradine OR
    c) nicorandil
    (decide based on comorbidities, contraindications, patient’s preferences and drug costs)
  • do not routinely offer other anti-anginal drugs other than CCB and BB routinely
26
Q

What is the first line treatment for angina?

A

BB or CCB

27
Q

What are the side effects of beta blockers?

A
  • worsens HF
  • reduces CO
  • increased vascular resistance (because b2 receptors are vasodilation and their effect is blocked)
  • bradycardia
  • Heart block – decreased conduction through AV node
  • cold extremities
  • Fatigue*
  • Impotence (sexual dysfunction)*
  • Depression*
  • CNS effects (lipophilic agents) e.g. nightmares*

*not quite proven

28
Q

When do you have to be particularly careful when giving beta-blockers?

A
  • If the patient has HF
  • it can worsen HF (due to increased resistance and decreased CO)
  • if needed in HF you have to give it in a very controlled and monitored way gradually increasing the dosage
    Beta 2 receptor blockade will reduce vasodilation and increase TPR which can worsen heart failure.

Also in patients with:

  • asthma (beta activation causes dilation)
  • diabetes (beta 2 (and a1) is important for HGO; masks hypoglycaemia, if you were getting hypoglycaemic the SNS would give you a warning effect)
  • ❤️block (if someone has HB or any conductive problems, bradycardia could become a problem)
29
Q

Pindolol in HF and angina

A
  • has ISA (intrinsic sympathomimetic activity)
  • good for HF AND Angina
  • at rest, during daily activities it does not have much effect
  • beta-blocking effects kick in when you exercise
30
Q

Mixed blockers in angina

A
  • if you want to prevent the increased vascular resistance from being a problem
  • if you also give alpha blockade it will cause dilation rather than constriction
  • this can also help a bit with HF
  • e.g. carvedilol (b1,b2,a1)
31
Q

Why do beta-blockers cause cold extremities?

A
  • Loss of β2 receptor mediated cutaneous vasodilation in
    extremities
  • removing this vasodilation capacity makes it hard for blood to reach the fingers
32
Q

What are the questionable/not quite proven SEs of beta blockers>

A
  • Fatigue
  • Impotence (sexual dysfunction)
  • Depression
  • CNS effects (lipophilic agents) e.g. nightmares

=> evidence base is not fantastic, RCTs would be needed

33
Q

What are the side effects of verapamil?

A

=> CCB (rate-slowing)

  • constipation (annoying but not dangerous) -> in 25% patients (gut Ca2+ channel block)
  • bradycardia and AV block (Ca2+ channel block)

less dangerous SE profile than BB

34
Q

What are the side effects of dihydropiridines?

A

=> CCB (non-rate-slowing; e.g. amlodipine)
-> you don’t tend to use these in angina.

They are very effective at vasodilation: you tend to get vasodilating side effects.

In 10-20% patients:

  • ankle oedema
  • flushing/headaches (due to vasodilation in the brain)
  • palpitations (reflex sympathetic response, baroreceptors increase HR)
35
Q

What are arrhythmia?

A
  • Abnormalities of cardiac rhythm (arrhythmias/dysrhythmias)
  • May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate (tachyarrhythmias).
  • affect around 700,000 people in UK.
36
Q

What are the aims in treatment of arrhythmias?

A

Reduce sudden death (e.g. sudden cardiac arrest)
Prevent stroke (clots)
Alleviate symptoms

Management is complex; usually undertaken by specialists; and may involve cardioversion, pacemakers, catheter ablation therapy and implantable defibrillators as well as drug therapy

37
Q

What is a simple classification of arrhythmias?

A

Based on site of origin:

  • Supraventricular arrhythmias (e.g. amiodarone, verapamil)
  • Ventricular arrhythmias (e.g. flecainide, lidocaine).
  • Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).
38
Q

Vaughan Williams Classification

A

Classification of Arrhythmic drugs

  1. Na+ channel blockade
  2. beta-adrenergic blockade
  3. Prolongation of repolarisation (membrane stabilisation; mainly due to potassium channel blockade)
  4. CCB

=> classification is of limited clinical significance

39
Q

Adenosine

A
  • Used intravenously to terminate supraventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil.
  • if you slow the heart down there is a greater chance of restoring normal rhythm,
40
Q

MOA of Adenosine

A
  • binds to A1R on SA and AV node cells: causes decrease in cAMP which decreases HR and dromotropy (conduction speed)
  • binds to A2R on (coronary) vascular smooth muscle, increases ic cAMP and causes relaxation
41
Q

Verapamil in arrhythmias

A
  • Reduction of ventricular responsiveness to atrial arrhythmias
  • preferred to adenosine in asthma
  • rate-slowing CCB
42
Q

MOA of verapamil in arrhythmias

A
  • Depresses SA automaticity and subsequent AV node conduction
  • block the calcium channels and decrease the ability to depolarise and try to restore normal rhythm
43
Q

Amiodarone

A
  • can be used in a number of different arrhythmias
  • superventricular and ventricular tachyarrhythmias – often due to reentry
  • can be used for tachyarrhythmais associated with wolff-parkison-white syndrome
  • MOA:
  • Complex action probably involving multiple ion channel block
  • mainly blocks potassium channels and prolongs repolarisation (likelihood that a re-entry rhythm causes contraction reduces because the cells are still in repolarising state)
44
Q

Re-entry arrhythmias

A
  • you can get areas of dead or damages tissue and the AP can travel in the wrong direction (dead tissue seems to be unidirectional)
  • If you have this dead tissue, the AP can move up and it can reactivate the tissue -> more likely to have jerky contraction (not relax-contract-relax-contract…)
  • not every re-ernty rhythm automatically causes contraction (it depends on what state the cardiac tissue is in when it gets there)
45
Q

Does every re-ernty rhythm cause contraction?

A

No

-> it depends on what state the cardiac tissue is in when it gets there

46
Q

What are adverse effects of amiodarone?

A

Amiodarone accumulates in the body (t½ 10 - 100days)
Has a number of important adverse effects including:
- photosensitive skin rashes
- hypo- or hyper-thyroidism
- pulmonary fibrosis

=> be careful with this drug because it has dangerous Uses and it accumulates. Use it in very controlled situations.

47
Q

Re-entry rhythms and amiodarone

A
  • you are not stopping the re-ernty rhythms
  • by prolonging the repolarisation you are decreasing the probability that they will cause contraction because a re-entry rhythm won’t cause contractions if the cells are in a depolarising state
48
Q

Digoxin drug type

A
  • Cardiac glycoside
  • slows ventricular responses in
  • used in atrial fibrillation and atrial flutter
  • used in AF with stroke risk
  • makes heart beat slower but more powerfully
49
Q

MOA of digoxin

A
  • Inhibition of Na-K-ATPase (Na/K pump).
  • This results in increased intracellular Ca2+ via effects on Na+/Ca2+ exchange → positive inotropic effect
  • increase in Ca2+ is because there is a NA+/Ca2+ exchanger and if the NA+/K+ ATPase is working less there is Ca2+ accumulation
  • It also has PS like effects -> slows the heart down more rhythmical contractions, also each contraction is more powerful and also improivng CO.
  • central vagal stimulation causes increased refractory period and reduced rate of conduction through the AV node
50
Q

What are adverse effects of digoxin?

A
  • dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
  • Note: Hypokalaemia (usually a consequence of diuretic
    use) lowers the threshold for digoxin toxicity because they compete for the same site
51
Q

Why should you be careful when giving digoxin in hypokalaemia?

A
  • digoxin and K+ bind to the same binding site
  • in hypokalaemia digoxin toxicity is more likely
  • so always watch the patients potassium levels.
52
Q

What is the threshold of the AP in the heart?

A

-30 mv

53
Q

What are the effects of the SNS and PNS on the heart AP?

A

SNS: ↑ cAMP, ↑ If & Ica

PNS: ↓ cAMP, ↑ IK

54
Q

Phenylalkylamines

A
  • (e.g. Verapamil)
  • Rate slowing calcium antagonist
  • (Cardiac and smooth muscle actions)
55
Q

Benzothiazepines

A
  • (e.g. Diltiazem)
  • Rate slowing calcium antagonist
  • (Cardiac and smooth muscle actions)
56
Q

Name some rate slowing calcium antagonsits

A

Phenylalkylamines (e.g. Verapamil)

Benzothiazepines (e.g. Diltiazem)

57
Q

Dihydropyridines

A
  • (e.g. amlodipine)
  • non-rate slowing Calcium channel antagonist
  • smooth muscle actions – more potent
  • No effect on the heart. Profound vasodilation can lead to reflex tachycardia
58
Q

Example of a non rate slowing calcium channel antagonist

A

Dihydropyridines (e.g. amlodipine)

59
Q

You shouldn’t prescribe beta blockers if a patient has the following confitions

A
  • DM
  • HF
  • Asthma

Year 2 - LCRS - Pharmacology (34 decks)

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