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LCRS Pharma > Drugs and the CVS: Heart > Flashcards

Drugs and the CVS: Heart Flashcards

1
Q

what are the channels involved in reaching the threshold for the AP i.e. the pacemaker potential?

A

1) [I]f (funny channel) : mixed current; slow spontaneous depolarisation due to a mix of Na+ and K+
- initial and end of the potential

2) [I]Ca (fast calcium influx) depolarisation:
- Na+ inactivated; produces slow conduction velocity

3) [I]K (potassium) repolarisation:
- K+ is effluxed
- Ca2+ inactivated

NB pacemaker potentials don’t have a true resting potential (it begins from a lower mV to that of myocardial potentials)

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2
Q

what is the effect of the SNS on cAMP and the channels?

A

increases cAMP

increases [I]f and [I]ca (promote AP)

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3
Q

what is the effect of the PNS on cAMP and the channels?

A

decreases cAMP

increases [I]k

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4
Q

what are the actions of PKA activated by cAMP?

A

o Phosphorylates proteins in the myofibril.

o Induces CICR in the SR by stimulating Ca2+ influx into SR.

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5
Q

what are the proportions of calcium provided by depolarisation-induced Ca2+ influx and by CICR?

A

The majority (75-85%) of Ca2+ is from CICR

20-25% comes from DICR

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6
Q

what is activated to cause the increase in cAMP during beta 1 stimulation?

A

adenylate cyclase

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7
Q

what mediates the removal of calcium post-contraction?

A

(1) Plasma membrane Ca2+ ATPase (ATPase Ca2+ channel)
(2) Sodium Calcium Exchanger (Na+/Ca2+ exchanger)

mediate removal of Ca2+ from the cells.

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8
Q

what part of the heart drives heart rate?

A

SAN (start of electrical activity)

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9
Q

what is the main ion driving heart APs?

A

calcium

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10
Q

what is the role of “funny channels” ?

A

initiate depolarisation

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11
Q

what contraction is the primary determinant of myocardial oxygen demand?

A

myocyte contraction

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12
Q

what needs to be done to meet:

  • increased HR?
  • increased after load/contractility?
  • increased preload?
A

(1) increased contractions
(2) increased force contractions
(3) small increase force of contractions

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13
Q

what factors affect myocardial oxygen supply?

A

(1) coronary blood flow

(2) arterial oxygen content

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14
Q

what drugs affect heart rate? [3]

A
  • Beta blockers (beta 1)
  • calcium channel antagonists
  • ivabradine (blocker of funny channels to slow depolarisation)
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15
Q

what is the effect of beta blockers on the pacemaker potential channels?

A

decrease [I]f and [I]ca

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16
Q

what is the effect of calcium channel antagonists on pacemaker potential channels?

A

decreases [I]ca

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17
Q

what is the effect of ivabradine on pacemaker potential channels?

A

decreases [I]f therefore prolongs the slow depolarisation phase (4)

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18
Q

what is the overall effect of drugs affecting heart rate on the AP?

A

prolong depolarisation by spacing it so decreases HR

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19
Q

what drugs affect contractility?

A
  • beta blockers

- calcium channel antagonists

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20
Q

what is the effect of beta blockers on contractility and how is this achieved?

A

decreases contractility by reducing phosphorylation and cross-bridge formation

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21
Q

what is the effect of calcium antagonists on contractility and how is this achieved?

A

block VG L-type calcium channel of:

  • cardiac (non-dihydropyridine/rate slowing)
  • smooth muscle (dihydropyridine/non-rate)

stops further entry of calcium into the myofibrils

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22
Q

what are the two classes of calcium antagonists?

give examples

A

(1) non-dihydropyridines
- ->rate slowing
- phenylalkylamines e.g. Verapamil –> affect SAN
- benzothiazepines e.g. diltiazem

(2) dihydropyridine
- -> non-rate slowing
- e.g. amlodipine

remember that verapamil affects pacemaker nodes therefore must be a rate affecting CCB

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23
Q

where do rate-slowing and non- rate slowing calcium antagonists have their effects?

A
  • rate slowing: cardiac tissue and VSM

- non-rate slowing: VSM only and therefore more potent on it. These have no effect on the heart itself

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24
Q

what is the effect of such a potent drug class like dihydropyridine?

A

reflex tachycardia due to extensive vasodilation:

its effect being purely on VSM means that profound vasodilation causes a reflex tachycardia

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25
Q

what drugs affect myocardial oxygen supply/demand?

A

(1) organic nitrates

(2) potassium channel openers

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26
Q

how do organic nitrates affect myocardial oxygen supply/demand?
e.g. nitroglycerin

A

1) Increases oxygen supply by increasing coronary blood flow by increasing smooth muscle relaxation
2) increased venous blood return due to vasodilation of veins more than arteries

smooth muscle relaxation:

  • directly supply NO
  • increases cGMP
  • stimulates K+ channel opening
  • therefore relaxation due to hyperpolarisation
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27
Q

how do potassium channel openers affect myocardial oxygen supply/demand?

A

stimulates hyperpolarisation and therefore the ability for coronary arteries to contract is impaired

the other drug affecting myocardial supply and demand are organic nitrates (different mechanism)

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28
Q

what is the overall effect of the drugs that impact myocardial oxygen supply/demand?

A

decrease demand:decrease preload (due to venous dilation) decrease after load (due to arterial dilation) and therefore demand for oxygen

increase supply: increase coronary blood flow and therefore increase oxygen supply

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29
Q

what is angina a mismatch of?

A

myocardial supply and demand of oxygen

causes myocardial ischaemia

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30
Q

what is the treatment plan for angina normally?

A

aim: to reduce the work of the heart as there’s a mismatch of demand and supply

1) beta-blocker or CCA as background treatment (first line).
2) Nitrate for symptomatic treatment (i.e. exercise)
3) Ivabradine – new more specific treatment.
4) Other – e.g. K-channel openers if intolerant to other drugs

Nicorandil
these are second line

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31
Q

what is the effect of beta blockers on heart failure?

A

worsens it due to reduction in cardiac output and increased vascular resistance when beta 2 receptors are blocked

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32
Q

what are the main adverse effects of beta blockers?

A
  • bradycardia (beta 1)
  • bronchoconstriction (beta 2)
  • hypoglycaemia (beta 2)
  • cold extermities (Raynaud’s; beta 2)
  • worsening peripheral artery disease (beta 3)
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33
Q

what causes the bradycardia as a side effect of beta blockers?

how is it resolved?

A
  • heart block
  • decreased AV conduction

(binding to beta 1 responsible for increase HR)

resolution: provide Pindolol (ISA)
- mixed alpha and beta blockers e.g. carvedilol, with vasodilator activity

34
Q

what are the less obvious, doubted side effects of beta blockers?

A

fatigue, impotence, depression and CNS effects (e.g. nightmares

35
Q

how do beta blockers cause cold extremities?

A

loss of beta 2 mediated cutaneous vasodilation in the extremities

36
Q

how does the CCB side effect profile compare to that of beta blockers?

A

less dangerous

37
Q

what are the side effect of the rate-slowing CCB Verapamil?

A
  • bradycardia and AV block: due to blockage of cardiac Calcium channels
  • constipation :due to blockage of gut calcium channels
  • hyperprolactinaemia
38
Q

what are the side effects of non-rate slowing CCB (dihydropyridines)?

similar effects seen in potassium channel openers and nitrates…

A

e.g. amlodipine: as a non-rate slowing drug it targets vessels rather than myocardium therefore side effects are due to VASODILATION
1) ankle oedema:
due vasodilation increase capillary pressure
2) headache/flushing
these are both due to vasodilation
3) palpitations (reflex)
as a reflex SNS effect in response to vasodilation
4) reflex tachycardia:
due to vasodilation

39
Q

what are the aims of rhythms disturbance treatment?

A
  • reduce sudden death
  • reduce symptoms
  • prevent stroke
40
Q

what are the 3 type of arrhythmia based on site of origin?

A

(1) supra ventricular
(2) ventricular
(3) complex (supra- and ventricular)

41
Q

what drugs can be used for each of the 3 types of arrhythmias?

A

((1) supra ventricular - amiodarone, verapamil

(2) ventricular- flecainide, lidocaine
(3) complex (supra- and ventricular) - disopyramide

42
Q

what are the 4 classes in the Vaughan Williams classification of drugs?
NBKC

A 
Class 1 
– Na+ channel blockade.
Class 2
 – Beta-blockers.
Class 3 
– prolongation of repolarisation mainly by K+ channel blockade
Class 4 
– Ca2+ channel blockade.
43
Q

why is the Vaughan Williams classification clinically insignificant?

A

the drugs overlap in properties and can’t be strictly put into classes

44
Q

Name 4 selective anti-arrhythmics used in Vaughan-Williams classification?

A

(1) adenosine
(2) verapamil (non-dihydropyridine CCB)
(3) amiodarone (K+ channel blocker)
(4) digoxin (digitalis)

45
Q

what is the effect of adenosine at its two main target sites?

1) SA and AV nodes
2) Vascular smooth muscle

Class V

A

1) in SA and AV nodes
- acts on adenosine type 1 receptors
- causing a decrease in cAMP
- therefore decrease in ionotropy and chronotropy

2) it can also target VSM (to a smaller extent)
- binding to adenosine type 2A receptors
- by increasing cAMP inhibits myosin light chain kinase
- cause relaxation

NB caffeine is an adenosine receptor antagonist

46
Q

what is the effect of verapamil?

Class IV

A

impact on pacemaker nodes (needed for their autonomic nature) :

  • reduces ventricular responsiveness to atrial arrhythmias
  • blocks VGCC and thus depresses SA firing and subsequent AV node conduction.
47
Q

what is the effect of amiodarone?

Class I, II, III, IV

A

Most likely prolongs hyperpolarisation which reduces chance of re-entry causing depolarisation.
- in SVT and VT with re-entry; conduction loops back to tissue that shouldn’t be depolarised causing jerky contractions

probably involving multiple ion-channel block.

48
Q

what are the adverse effects of amiodarone?

A

o Accumulation in body.
o Skin rashes (photosensitive).
o Hypo- or hyper-thyroidism.
o Pulmonary fibrosis.

49
Q

what type of drug is digoxin?

A

cardiac glycoside targeting transport systems, namely Na/K ATPase

50
Q

what is the use of digoxin?

A

atrial fibrillation and atrial flutter

-these impair ventricular filling and reduce CO

51
Q

what is mechanism of action digoxin?

A

Inhibits the Na/K ATPase causes build up of calcium indirectly in the cell causing vagal stimulation (PNS) to the heart:

  • Na+/Ca2+ symporter allows enter and exit of Na+ and Ca2+ simultaneously
  • Na/K ATPase aims to move Na+ out in exchange for K+ coming in, so Ca2+ can enter with Na+ from the outside, into the inside
  • Na/K ATPase inhibition prevents Na+ exit but Na+ entry (with Ca2+) is under hindered
  • Na+ builds up in the cell, conc gradient shifts towards the cell so calcium also builds up in the cell

increase inotropy–> vagal stimulation to decrease HR, improving cardiac output and contractility

52
Q

what is the effect of central vagal stimulation caused by digoxin?

A

increased refractory period due to reduced removal of Ca2+ post contraction

reduced rate of conduction via AVN so fewer impulses reach the ventricles

53
Q

what is a harmful effect of administering diuretics with digoxin?

A
  • diuretics cause hypokalaemia (increased removal of potassium in exchange for sodium)
  • this reduced the threshold to cause digoxin toxicity
  • potassium competes with digoxin at the Na/K ATPase
  • so low potassium levels mean more digoxin can bind at the site and its effects can be enhanced
54
Q

what maintains the sodium gradient once calcium has been effluxed with sodium after contraction?

A

Na+/K+ ATPase maintains the sodium gradient by allowing sodium out of the cell in exchange for potassium so it can move back into the cell with Ca2+

55
Q

what is used to approximate preload?

A

the ventricular EDV

dependent on venous tone and circulating blood volume

56
Q

what is used to approximate afterload?

A

MAP

57
Q

what CVS features do drugs of the heart target?

A
  • heart rate
  • contractility
  • myocardial demand for oxygen and its supply
58
Q

what channels involved in pacemaker potential are affected by beta blockers?

A

remember: SAN drives heart rate and makes use of pacemaker potential

beta blockers decrease I[f] and I[Ca]

59
Q

what channels involved in pacemaker potential are affected by calcium antagonists?

A

decreased I[Ca]

60
Q

what channels involved in pacemaker potential are affected by ivabradine?

A

decreased I[f]

61
Q

describe the mechanism of action of beta blockers

A
  • Acts on the β-adrenergic receptors (β1 on the heart, β2 on vascular smooth muscle)
  • Decrease SA and AV nodal activity by ↓ cAMP, ↓ Ca2 currents.
  • Supress abnormal pacemakers by ↓ slope of phase 4
62
Q

what are the clinical uses of beta blockers?

A

supraventricular tachycardias namely:

  • atrial fibrillation (irregular, fast beating of atria)
  • atrial flutter (atria contract faster than ventricles)

these need ventricular rate control:

  • affect the rate
  • affect the contractility
63
Q

what are the main contraindications of beta blockers?

These contraindications are due to the unwanted effects of beta receptor blockage

A

1) beta blockers causes BRONCHOCONSTRICTION due to blockage of beta2 needed for bronchodilation
- asthmatics (bronchoconstriction)
- COPD (bronchoconstriction)

2) beta blockers cause HYPOGLYCAEMIA due to blockage of beta 2 preventing gluconeogeneis and glycogenolysis in the liver
- diabetics (hypoglycaemia)

3) beta blockers cause VASOCONSTRICTION due to blockage of beta 2 preventing vasodilation in skeletal muscles
- Raynaud’s (cold extremities)

NB beta 2 needed for: bronchodilation, vasodilation and increased glucose

64
Q

where do dihydropyridines (non-rate slowing) CCBs act?

A

on vascular smooth muscle

e.g. amlodipine, clevidipine

your “-pines”

65
Q

where do non-dihydropyriidnes (rate slowing) CCBs act?

A

on the heart e.g. verapamil and diltiazem and to some extent on VSM

66
Q

what are the clinical uses of CCBs?

A

1) dihydropyridines (non-rate slowing):
hypertension
angina
Raynauds (cold extremities)

2) non-dihyrdopyridines (rate slowing):
hypertension 
angina
atrial fib 
atrial flutter
67
Q

what is the mechanism of action of ivabradine?

A

N.B. used for reducing heart rate

IVabradine prolongs slow depolarization (phase IV) by selectively inhibiting the funny channels If

68
Q

what are the clinical uses of ivabradine?

A
  • chronic stable angina (those who can’t use beta blockers)

- heart failure, reduced ejection fraction 1

69
Q

what are the adverse effects of ivabradine?

A
  • Luminous phenomena/Visual brightness
  • Hypertension
  • Bradycardia
70
Q

what is the mechanism of action of organic nitrates like nitroglycerin?

A
  • Vasodilate by ↑ NO in vascular smooth muscle
  • ↑ in cGMP and smooth muscle relaxation leading to increased coronary blood flow
  • Dilate veins&raquo_space; arteries. ↓ preload

organic nitrates aim to increase coronary blood flow and decrease preload (therefore increase myocardial o2 supply)

71
Q

how do organic nitrates increase the myocardial oxygen supply and reduce the myocardial oxygen demand?

A
  • increase in supply: vasodilation and smooth muscle relaxation increases coronary blood flow
  • decrease in demand: organic nitrates dilate veins more than arteries. This reduces the preload on the heart. Preload is dependent on the venous system
72
Q

what are the clinical uses of organic nitrates?

A

Angina
Acute Coronary syndrome
Pulmonary Oedema

73
Q

what are the adverse effects of organic nitrates?

A
  • Reflex tachycardia (treat with B-blockers)
  • Hypotension
  • Flushing
  • Headache

due to excessive smooth muscle relaxation and venous vasodilation

74
Q

what is the mechanism of action of potassium channel openers?

A

↑ AP duration
↑ Effective refractory period
↑ QT interval
↑ coronary blood flow

75
Q

what are the clinical uses of potassium channel blockers?

A

atrial fib
atrial flutter
ventricular tachycardia

76
Q

what are the adverse effects of potassium channel openers?

A

torsade de pointes

77
Q

name a potassium channel blocker (BLOCKER not opener)?

A

amiodarone

78
Q

simple mechanism of action of digoxin

A

indirect blockage of Ca2+ removal post contraction (i.e increased calcium conc in the cell)

  • Direct inhibition of Na+/K+ ATPase
  • indirect inhibition of Na+/Ca2+ exchanger
  • ↑ [Ca2+]I therefore positive inotropy
  • Stimulates vagus nerve therefore ↓ HR
79
Q

what are the adverse effects of digoxin?

A
  • Cholinergic effects (nausea, vomiting, diarrhea)
  • Blurry yellow vision
  • Arrhythmias
  • AV Block
  • Can lead to hyperkalaemia which indicates a poor prognosis
80
Q

what part of Na/K ATPase does digoxin affect?

what effect does hypokalaemia have on digoxin?

A

K+ receptor competitive antagonist

  • hypokalaemia can enhance digoxin effects
  • Na/K ATPase is inhibited by digoxin so less sodium can leave the cell as no potassium enters
81
Q

why should beta blockers not be given to diabetics?

what alternatives can be given for hypertension?

A

1) bind to β2 receptors are found on the liver:
–> therefore antagonising the receptor prevents hypoglycaemia
(which is the increase in HGO)
2) bind to β1 receptors on the heart
–> decrease palpitations, therefore masking the symptoms of hypoglycaemia (hypoglycaemia causes SNS symptoms like palpitations normally )

alternatives:
ACEi
ARBs

LCRS Pharma (32 decks)

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