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PH2501- pharmacology > Lec 23- inotropes > Flashcards

Lec 23- inotropes Flashcards

1
Q

Inotropes

A
  • Increase cardiac force
  • Inotropes are used to support failing heart
  • The heart may fail in several circumstances and a variety of drugs may be used to support it
  • HR is effected by chronotropes
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2
Q

HF

A
  • HF is condition that develops when the hears muscle becomes weakened after injury
  • This can be from high BP, and loses its ability to pump sufficient blood to supply the bodies needs
  • On a frank-starling curve a failing heart will see decreased CO and more EDV
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3
Q

HF risk factors

A
  • AMI
  • High BP
  • High ChE
  • Damage to heart valves
  • Diabetes
  • Obesity
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4
Q

Mechanism responsible for HF

A
  • Decreased energy production
  • Increased energy utilisation
  • Abnormal Ca homeostasis
  • Altered gene expression
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5
Q

Compensatory mechanisms in HF

A

A) Frank-Starling
B) Neuroendocrine response: increase sympathetic output; increased RAAS activity; increased ADH (vasopressin)
C) Myocardial hypertrophy

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6
Q

Inotropes can be divided into the following classes

A
  • Cardiac glycosides: digoxin
  • Catecholamines: NA and adrenaline
  • Phosphodiesterase inhibitors- sildenafil
  • Calcium entry promoters- : opposite of CCB. Act on nitrendipine receptors
  • Ca
  • Ca sensitisers- increase affinity of troponin for calcium (depressed by hypoxia and acidosis). Potential future development (potential advantage that they wouldn’t increase myoplasmic Ca, therefore pherhaps less problems with arrhythmias)
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7
Q

Factors involved in cardiac contraction

A
  • AP OR
  • NA acts on B1-adrenoceptors (dobutamine act on these) resulting in phosphorylation (PKA pathway) of Ca2+ channels which increases opening times
  • 1) Depolarisation allows Ca2+ influx through voltage gated Ca2+ channels
  • 2) Ca2+ release from sarcoplasmic reticulum (SR) increases Ca2+ still further
    3) Ca2+ plus troponin= contraction
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8
Q

Mechanism for decrease of Ca2+

A

1) Ca2+ is extruded in exchange for Na by Ca2+ exchanger (CE)
2) Na+ is exchanged with K+ by the Na/K/ATPase (Na pump;SP)
- Cardiac glycosides inhibit the Na pump leading to: slow removal of Ca2+ so increasing concentration –> increasing force of contraction

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9
Q

Muscle cell: cardiac or vascular

A
  • AP
  • Open Ca channels
  • Influx of Ca2+
  • These act on SR channels
  • This causes further release of Ca2+
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10
Q

Inotrope action

A
  • Inotrope action involves Ca2+ handling in the cardiac myocyte
  • Rationale is to increase Ca2+ available of contractile proteins
  • This is done by: increase Ca2+ influx; Decreasing Ca2+ efflux
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11
Q

Increasing Ca2+ influx

A
  • B-adrenergic activation- dobutamine

- Phosphodiesterase inhibition- sildenafil

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12
Q

B-Aadrenergic activation

A
  • Activation of B1 receptors, leads via adenylate cyclase which turns ATP to cAMP. cAMP activates Protein Kinase A (PKA)
  • PKA phosphorylates L-type Ca2+ channels, which favours mode 2 gating (Opens them, also opens them for longer)
  • Amount of Ca2+ entry during depolarisation is therefore increased
  • Increased Ca2+ also means that more is stored in the sarcoplasmic reticulum for subsequent release
  • Post synaptic B1-receptors are predominant adrenergic receptors in the heart
  • Stimulation causes increased rate and force of cardiac contraction. mediated by cAMP
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13
Q

3 modes of Ca2+ channel opening

A 
-Mode 0
opening probability is 0 
Favoured by DHP antagonists 
% of time spent like this=<1%
-Mode 1
Opening probability is low 
%of time spent like this=70%
-Mode 2- This is the mode when opened by B-agonist 
Opening probability is high 
Favoured by DHP agonists 
%of time spent like this=30%
-Weather or not a channel is open affects the binding of the drug
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14
Q

In addition to causing increased Ca2+ entry

A
  • B1 adrenoceptors activation also leads to an increase of the sensitivity of the contractile machinery, probably via troponin C phosphorylation
  • There is also more cytosolic Ca2+ for uptake into the SR, so that there is more Ca2+ for release during the AP
  • Net result is to elevate and steepen the ventricular function curve
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15
Q

B-receptors

A
  • Post synaptic B1 receptors are predominant adrenergic receptors in heart
  • Stimulation causes increased rate and force of cardiac contraction
  • Mediated by cAMP
  • Post synaptic B2-receptors in vasculature mediate vasodilation
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16
Q

a1-receptors

A
  • Post synaptic cardiac a1 receptors:
  • Stimulation cause ssignificant increase in contractility without an increase in rate
  • Mediated by IP3- Ca2+ release
  • Effect more pronounced at low HR
  • Slower onset and longer duration than B1-receptors mediated response
17
Q

Dobutamine

A
  • B1 agonist
  • IV continuous infusion in acute severe HF; infarction; cardiac surgery; cardiomyopathy; septic shock; cariogenic shock and during positive expiratory pressure ventilation
18
Q

Adrenaline/Epinephrine

A
  • Agonist at a and B receptors, net effect is Inotropic

- Iv continuous infusion I cardiopulmonary resuscitation; anaphylaxis; acute hypotension

19
Q

Phosphodiesterase inhibitors

A
  • In cardiac muscle PDEIII catalyses breakdown of cAMP
  • Inhibiting PDE III leads to increased levels of cAMP
  • Increased activation of PKA
  • Increased phosphorylation of L-type Ca2+ channels leads to more Ca2+ entry on depolarisation and so underlies the Inotropic effect
20
Q

Phosphodiesterase inhibitors 2

A

-increased Ca2+ influx increases rate and force of myocardial contraction
-cAMP also affects diastolic heart function through enhanced Ca re-sequestration rate and hence improves diastolic relaxation
-Synergistic with beta agonists
-Also relax vascular smooth muscle resulting in vasodilation
-Myocardial O2 consumption and HR are not significantly increased
-Tolerance is not a feature
NB different variants of PDE

21
Q

Enoximone and milrinoe

A
  • USE: management of decompensated CHF
  • Ademonstration: IV; (ITU or CCU)
  • Monitoring: BP; ECG: platelets; K+; CVP
  • Adverse effects: arrhythmias; hypersensitivity; hypotension
22
Q

Decreasing Ca2+ efflux

A
  • Na/K/ATPase inhibition
  • Ca2+ is extruded in exchange for Na by the Na/Ca2+ exchanger
  • Depends on Na gradient; Na is maintained low internally by Na/K/ATPase pump
  • By maintaining high conc of Na inside the cell this means that the Na/Ca exchanger can’t work as effectively which means that Ca2+ stays inside the cell for longer
23
Q

Cardiac glycosides

A
  • Inhibit Na/K/ATPase
  • Digoxin from digitalis purpurea (foxglove)
  • Na gradient is maintained bt ATPase pump
  • Na gradient drives Ca/Na
  • Reduced Na gradient slows Ca removal (by inhibition of ATPase)
  • NB due to the fact that we can’t pump out Ca2+ it is stored in sarcoplasmic reticulum
24
Q

Digoxin mechanism

A

-Inhibits Na/K/ATPase and produces subtle changes in resting electrolyte status
-Increase [Na]i
Increased [Na]I reduces driving force for Ca efflux and thereby increased Ca2+ loading in the SR (positive inotropic effect)
-Decreases [K]i
-Lowers resting membrane potential (i.e. more +ve), makes them more excitable and more likely to depolarise

25
Q

Digoxin

A
  • Increases contractility: positive inotrope; used for HF treatment
  • Decreased HR: Negative chronotrope; Used to control HR in AF
  • Monitoring; ECG: pulse; renal function; K; symptoms of toxicity; TDM
26
Q

Parasympathetic effects of cardiac glycosides

A
  • Reduces HR
  • Acts on Vagus nerve; the lowering of the resting membrane potential means the nerve is more excitable
  • Therefore release more ACh (inhibitory effect)
  • This acts on the SAN causing heart rate to slow down
27
Q

Frank starling curve- failing heart

A
  • A failing heart is unable to pump enough blood to meet the bodies demands
  • Due to decrease in the contractility of the left ventricle heart mule
  • Seen in the frank starling curve as a decrease in CO relative to ventricular filling

PH2501- pharmacology (47 decks)

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