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Pharmacology RDT Autumn term > Drugs and CVS: the heart > Flashcards

Drugs and CVS: the heart Flashcards

1
Q

Name the factors that control heart regulation

A
  1. Heart rate
  2. Contractility
  3. Myocardial oxygen supply
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2
Q

Describe the pacemaker cells of the SAN

A

Cells within the SAN are the primary pacemaker site within the heart. These cells are characterised as having no true resting potential, but instead generate regular, spontaneous action potentials.

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3
Q

What is the main difference between pacemaker and non pacemaker cells’ action potentials?

A

For pacemaker cells, the depolarising current is carried into the cell by the much slower Ca2+ currents instead of by the fast Na+currents. There are, in fact, no fast Na+ channels and currents operating in SAN.

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4
Q

What is the funny current

A

If- hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels. They switch on during hyperpolarised states, utilising cAMP and drive Na entry to initiate depolarisation.

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5
Q

What is Ica?

A

Ica (t or l)- transient t-type calcium channel or long-lasting L type. It mediates fast calcium influx.

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6
Q

What is Ik?

A

potassium channels opened when depolarisation reaches the postive end and then repolarisation occurs.

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7
Q

What is phase 4?

A

is the spontaneous depolarisation (pacemaker postential that trigger s the action potential).

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8
Q

Describe what happens on the spontaneous AP initation from the SAN

A
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9
Q

How is contraction brought about in the after APs have been initiated in pacemaker cells?

A
  1. Electrical excitation of the cell from Aps arising from the SAN induce membrane depolarisation that promote gating of Ca channels.
  2. Voltage gated Ca channels open and Ca enters the cell
  3. The small Ca current induces a release of Ca by binding to the ryanodine receptor-channels (RYR)- this is depolarisation.
  4. The binding to the RYR causes a calcium induced calcium release. CICR comes out of channels called ryanodine receptors (RYR2) from the sarcoplasmic reticulum.
  5. The Ca bind to troponin to initiate contraction.
  6. Relaxation happens when Ca unbinds from troponin and Ca is pumped back into the sarcoplasmic reticulum for storage.
  7. Ca is exchanged with Na via exchange proteins.
  8. The Na gradient is maintained with Na/K pumps.
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10
Q

How much of the required calcium needed for contraction come from outside the cell?

A

25%

the other 75% comes from CICR (the sarcoplasmic reticulum)

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11
Q

What happens when beta 1 receptors are stimulated?

A

When beta 1 adrenegic stimulation happens, adenyl cyclase is activated which creates cAMP which activates PKA. PKA has two actions:

  1. Phosphorylates proteins in the myofibril
  2. Induces CICR in the sarcoplasmic reticulum stimulating Ca influx.
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12
Q

What 2 channels/proteins are involved with calcium removal from inside the cell?

A

PMCA (ATPase Ca2+ channel) and NCX (Na/Ca exchanger) mediate the removal of Ca from cells.

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13
Q

What does the myocardial oxygen supply/ demand mean?

A

It is all about the balance between myocardial oxygen supply and myocardial oxygen demand. As long as they are balanced, there are no problems.

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14
Q

What is the primary determinant of myocardial oxygen demand?

A

Myocyte contraction

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15
Q

Which three factors will increase contractions of myocytes?

A
  1. Increased HR
  2. Greater afterload/ contractility (will increase the force of contractions)
  3. Increased preload (if there is a lot of blood being returned to the heart, it needs to eject a larger volume out and therefore there is more myocardial work/ contractions)
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16
Q

What are the 3 drugs that influence HR?

A
  1. Beta-blockers- decrease If and Ica
  2. Calcium antagonists- decrease Ica à calcium drives heart rate!!
  3. Ivabradine- decrease If
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17
Q

What is the difference between the MOA of blocking the funny current (which beta-blockers and ivabradine do) and blocking the calcium channels

A

Blocking the funny current, you will reduce the speed at which depolarisation happens and therefore you will decrease HR (less direct than calcium channel block).

These drugs reduce HR by prolonging depolarisation. If or Ica will decrease the SNS drive.

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18
Q

What are the drugs influencing contractility?

A
  1. Beta blockers- decrease contractility (reduce phosphorylation and cross bridge formation). Sympathetically driven through the beta 1 receptor.
  2. Calcium antagonists- decrease Ica stops further entry of calcium into myofibrils.
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19
Q

What are the 2 classes of calcium antagonists?

A
  1. Rate slowing
  2. Non-rate slowing
20
Q

What do the rate slowing calcium antagonists act on and give examples of some drugs

A

Rate slowing (cardiac and smooth muscle actions)-

Phenylalkylamines (e.g. verapamil)

Benzothiazepines (e.g. diltiazem)

21
Q

What do the non-rate slowing calcium antagonists act on and give examples of some drugs

A

Non-rate slowing (smooth muscle actions more potent)-

Dihydropyridines (e.g. amlodipine)

22
Q

What is a profound side effect of non-rate slowing calcium channel antagonists?

A

Although the non-rate slowing drugs have no direct effect on the heart, the profound vasodilation produced in response can lead to a REFLEX TACHYCARDIA. Reflex mediated by baroreceptor action.

23
Q

Name the 2 types of drugs that control myocardial oxygen supply and demand

A
  1. Organic nitrates
  2. Potassium channel openers
24
Q

How do organic nitrates help to control myocardial oxygen supply and demand?

A

Organic nitrates directly supplies NO, a powerful vasodilator. This increases cGMP which stimulates potassium channels into opening and relaxation directly due to the influx of calcium.

25
Q

How do potassium channel openers help to control myocardial oxygen supply and demand?

A

Potassium channel openers stimulate hyperpolarisation (ability of coronary arteries to contract is impaired)

26
Q

How do organic nitrates and potassium channel openers help to increase coronary blood flow?

A

They lead to venodilation (dilation which is uncontrolled) and vasodilation.

Both of these drugs increase coronary blood flow and decrease afterload and preload.

VASODILATION- will lead to decreased afterload (TPR)

VENODILATION- will lead to decreased preload

27
Q

What is the significance of the sGC enzyme?

A

sGC- the enzyme that produces cGMP. cGMP leads to muscle relaxation. Also causes potassium channel opening. If you have potassium efflux then it makes it difficult for the muscle to contract.

28
Q

What is stable angina?

A

It is like a cardiac stitch. If the heart is not receiving enough oxygen, you get pain. Usually comes with physical exertion. Seen in older people due to atherosclerosis (the blood cannot get through the vessels to the heart).

29
Q

What is the first line of treatment for stable angina?

A

Beta-blocker and calcium channel blocker are first-line treatment of angina as it massively reduces myocardial workload. It impedes on the patient’s ability to exercise.

Can use a long-acting nitrate, ivabradine or nicorandil.

30
Q

Why should you never give beta-blockers to people with heart failure?

A

Beta 2 receptor blockade will reduce vasodilation and increase TPR which can worse heart failure (as beta blockers will reduce CO). Heart failure cannot match CO to the demand. Beta blocker can help with angina but worsen heart failure. Beta 2 receptors are dilating receptors on smooth muscle so if they are blocked TPR will increase. Heart will have to work harder for ejection.

Bradycardia- leads to heart block (reduced conduction through AVN).

31
Q

Why should you never give beta-blockers to asthmatics?

A

Should not be given to someone with asthma due to its bronchoconstrictor properties.

32
Q

Why should beta blockers never be given to diabetics?

A

Should not be given to individuals with poor sugar control (diabetics). Beta-blockers cause glycogenolysis and gluconeogenesis. It will mask hypoglycaemia and there will be no early warning signs.

33
Q

What are the other side effects of beta-blockers (that have not been backed up by RCTs)?

A
  • Cold extremities- loss of beta 2 receptor-mediated cutaneous vasodilation in extremities
  • Fatigue
  • Impotence (sexual dysfunction)
  • Depression
  • CNS effects (lipophilic agents)-e.g. nightmares
34
Q

What are the side effects of rate-controlling calcium antagonists?

A

Verapamil-

bradycardia and AV block (as calcium channels are blocked)

Constipation (gut calcium channels are impacted- happens in 25% of patients)

35
Q

What are the side effects of non-rate-controlling calcium antagonists?

A

Dihydropyridines-

Ankle oedema- vasodilation means more pressure on capillary vessels

Headache/ flushing- vasodilation

Palpitations- mainly caused by the sympathetic stress response by baroreceptors. They get stressed by the vasodilation and increase HR.

Can have the vasodilation/ reflex adrenergic activation.

36
Q

What are rhythm disturbances of the heart?

A

Abnormalities of cardiac rhythm are common.

Aims of their treatment are to reduce the chance of sudden death, prevention of stroke and alleviate any symptoms. Stroke is likely to form if there is stagnant blood (not pumping properly and clots form).

37
Q

How are arrythmias managed?

A

Management of arrythmias is complex. It can involve cardioversion, pacemakers, catheter ablation and implantable defibrillators.

Arrythmias can be classified at their site of origin:

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

What is the Vaughan-William classification of anti-arrythmic drugs?

A
39
Q

What is the problem with the VW classification?

A

The problem- not a lot of drugs fall into these classes because they do several things. It has very limited clinical significance.

40
Q

What is adenosine used for?

A

Adenosine is used to target supraventricular arrythmias.

41
Q

What is the MOA for adenosine

A

In cardiac tissue, adenosine binds to type 1 receptors which are coupled to Gi proteins. Activation of the Giprotein opens potassium channel and causes hyperpolarisation but Gi also decreases the cAMP. cAMP is vital for driving the funny current and you reduce depolarisation through the SAN. The tissue has longer to repolarise.

The adenosine will inhibit the pacemaker current in the SAN, decreasing phase 4 of the pacemaker action potential, decreasing firing rate (negative chronotropy).

It is used IV on someone with supraventricular tachycardia (SVT). Its actions are short-lived, and it is safer than verapamil. Verapamil blocks calcium channels and decreases the ability to depolarise to restore normal rhythm. The main aim is to increase the time of depolarisation.

42
Q

What is amiodarone used for?

A

Amiodarone is used for supraventricular and ventricular arrythmias

43
Q

What is the MOA for amiodarone?

A

In normal tissue, AP passes down branches and moves to other parts of muscle. If they came across each other, the rhythms cancel each other out. If there is dead tissue, it will block the propagation of AP down a specific branch, preventing the cancelling out and the AP will carry on to re- activate the tissue. You end up with jerky contraction and there is no set relaxation.

Not every re-entry rhythm will cause contraction. Amiodarone prolongs the repolarisation phase by blocking potassium channels. The likelihood of re-entry reduces. Amiodarone it is not very safe- it accumulates in the body and it is very lipophilic. Has a number of severe adverse side effects.

44
Q

What is digoxin used for?

A

It is used for the treatment of supraventricular arrythmias (they are cardiac glycosides)

45
Q

What is the MOA of digoxin?

A

The drug acts to inhibit the Na-K-ATPase pump. This results in increased intracellular ca via effects on the Na/Ca exchange. Na builds up inside and is swapped for Ca.

There is a positive inotropic effect.

Digoxin also causes central vagal stimulation causes increased refractory period and reduced rate of conduction through the AV node. Fewer impulses reach the ventricles and the ventricular rate falls.

It is administered orally. It slows the ventricular response and is used in cases of atrial flutter and atrial fibrillation.

Atrial flutter and fibrillation can lead to a rapid ventricular rate that can impair ventricular filling.

Pharmacology RDT Autumn term (10 decks)

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