L2 CV pharmacology 1

Question 1

Positive inotropes

Answer 1

AIM:

1. increase contractility
2. Increase sympathetic Stimulation
3. Allow heart to stretch a littttle bit more. Means more Ca2+ released from sarcoplasmic reticulum

Question 2

How does preload affect contractility?

Answer 2

inc PL, inc EDVV, inc contractility

Question 3

How can we create positive inotropes pharmacologically

Answer 3

Something that:

1. Mimic or enhance sympathetic activity
2. Inc intracellular level of Ca2+
3. Inc EDVV theoretically – physiological effect, not really used pharmacology

Question 4

What drug groups are used due to their positive inotroph effect?

Answer 4

1. PDE III inhibitors
2. Sympathomimetics
3. Cardiac glycosides – can be but a bit controversial
   Last 2 not talk about but for awareness
   o (Anticholinergics)
   o (Glucagon)

Question 5

Where wouldn’t we use positive inotrophs?

Answer 5

1. Atrial fibrillation – want to dec contraction here
2. Hypertrophy
3. Aortic or pulmonary stenosis (narrowing), if use positive inotrope, putting more pressure on heart to contract. Not cool

Question 6

Role of phosphodiesterase III inhibitor (PDE III inhibitor)

Answer 6

It is a HEART specific phosphodiesterase

1. welllll, Phosphodiesterase degrades intracellular cAMP
2. So PDE INHIBITOR increases intracellular cAMP = inc contractility (+ve inotrope) = inc HR

Question 7

What effect will PDE III inhibition have on the cardiac myocyte

Answer 7

1. Increased intracellular cAMP which
2. Activates protein kinase A
3. This phosphorylates a site on the Ca channels, making them more likely to open
4. Increased flow of Ca into cardiomyocytes and increased Ca induced Ca release
5. Resulting in stronger contractions

Question 8

What other affects of PDE III that increases contractility

Answer 8

1. Vasodilation due to inc in cAMP in smooth muscle
   a) cAMP activates a kinase which phosphorylates myosin light chain kinase
2. Tachycardia - due to faster movement of Ca2+ into cell, therefore faster depolarisation. This is not really seen as much of an issue clinically

Question 9

What affect does cAMP have on cardiac and smooth muscle

Answer 9

1. Cardiac, cAMP causes contraction
2. Smooth = relaxation
   So:
   • Cardiomyocytes:
   a) If we inhibit PDEIII in cardiac muscle cells = more cAMP, inc contractility
   b) Leads to opening of Ca2+ channels = influx of Ca from sarcoplasmic reticulum, more contraction
   • Smooth muscle cells:
   a) Inhibits myosin light chain kinase = vasodilation, relaxation of smooth muscle!

Question 10

cAMP

Answer 10

o sympathetic effects on the heart occur through increased intracellular cAMP too!
o Inc cAMP – relaxation of smooth muscle AND contraction cardiomyocytes!

Question 11

Name PDEIII inhibitors in practise

Answer 11

1. Pimobendan (Vetmedin)

2. Cardiac Glycosides