Cardiovascular pharmacology 2 Flashcards
What are the endogenous mechanisms of positive inotropes?
- increase contractility
- sympathetic stimulation
- increase EDVV by increasing preload
How can we create the effect of positive inotropes pharmacologically?
- mimic/enhance sympathetic activity
- increase intracellular calcium
Which 3 drug groups are used to act as positive inotropes?
- PDE III inhibitors
- Sympathomimetics
- Cardiac glycosides
What happens when phosphodiesterase is inhibited?
Increase in intracellular cAMP (as it usually degrades it)
This leads to increased contractility
What effect will increased intracellular cAMP have in the cardiac myocyte?
- Activated protein kinase A
- This phosphorylates Ca channels, making them more likely to open
- Increased flow of Ca into cardiomyocyte + increased Ca induced Ca release
- Stronger contraction
What are the two other predictable effects of increased intracellular cAMP?
- Vasodilation: because of activated myosin light chain kinase
- Tachycardia: faster Ca flow into cell = faster depolarisation
Which PDE III inhibitor is used in practice, how is it administered?
Pimobendan
- Positive inotrope and vasodilator
- Oral or parenteral administration
What is the only cardiac glycoside in use?
Digoxin
What is the theory of the supposed positive inotropic effect of Digoxin?
- Inhibits the Na/K pump in cardiac myocytes which increases the intracellular Na
- Reduced Ca extrusion from the cell because there is a smaller gradient for Na to move into the cell
- Therefore more Ca moved into SR to be released during an action potential
By inhibiting Na removal from the cell, what other effect do you predict cardiac glycosides to have in the heart?
Negative chronotropy - major action of these drugs
What is the target of sympathomimetics?
β1 receptors on cardiac myocytes - agonist action will increase contractility
What are the three types of negative inotropes?
- Sympathetic antagonists
- Cholinergics
- Calcium channel blockers
A drug affecting perfusion will alter which 3 factors?
- CO
- Vascular diameter
- Circulating volume
Drugs affecting arterial pressure will alter which 2 factors?
- CO
- TPR
Why would we want to reduce preload?
Reduce congestion
Reduce oedema
Reduce work for the heart
Why would we want to reduce afterload?
Forward HF
Vasodilation
Reduce congestion
Why would we want to reduce systemic arterial pressure?
- Reduce afterload
- Organ failure will occur if there is chronic hypertension so this needs to be reduced
What are the 4 direct vasodilators?
- Nitrates
- Ca channel blockers
- PDE III inhibitors
- Hydralazine
Describe the effects of nitrates
- Cause peripheral vasodilation via nitric oxide action
- Leads to vasculature relaxation
Which 2 nitrates are used in practice?
- Nitroprusside
- Nitroglycerine
Ca channel blockers work as direct vasodilators, but are also in which other drug group?
Class IV antidysrhythmics
Describe the action of PDE III inhibitors
Used for chronic heart failure.
- Inhibit the breakdown of cGMP
- This activated protein kinase G
- This activates myosin light chain phosphatase
- Dephosphorylates myosin light chain which causes relaxation
Hydralazine acts as a …?
Arteriodilator
What are the 2 indirect vasodilators and through what method do they act?
- Sympathetic NS
- RAAS
- Extrinsic mechanism
Where do sympathetic antagonists act?
- non-specific
- can act at any point from the brainstem to peripheral receptors
What are the 2 sympathetic antagonists used in practice?
- Prazosin
- Phenoxybenzamine
What 2 bits of the RAAS cause vasoconstriction?
- Angiotensin II
- Stimulated ADH release
What else does the RAAS do that influences blood pressure and preload?
At the kidney it retains water and sodium ions
Which 3 conditions would benefit from RAAS blockade?
- Chronic heart failure
- Hypertension
- Chronic renal failure
What is the role of ACE?
Converts Angiotensin I to Angiotensin II
What do ACE inhibitors cause?
- Vasodilation
- Reduced circulating volume
- Thus, improved tissue perfusion
- Reduced preload
- Reduced systemic arterial pressure
Where are ACE inhibitors activated?
Liver
What are Aldosterone antagonists used for?
- Reduce retention of sodium and water, which also reduced K loss
- Reduced cardiac remodelling which is associated with aldosterone
What are the 2 aldosterone antagonists used in practice?
- Spironolactone
- Cardalis (Benazepril + spironolactone)
What other method can be used to reduce preload?
Diuretics
