Theme 3: Lecture 13 - Drug treatments for CVD 3 (ischaemic heart disease) Flashcards
Describe the mechanism of action where nitrates lead to relaxation of smooth muscle
- Nitrates (GNT) enter cell and are broken down into nitric oxide
- NO stimulate guanylyl cyclase to convert GTP into cGMP
- cGMP stimulate myosin light chain phosphatase to remove the phosphate group from phosphorylated myosin light chain to convert it into myosin light chain
- Myosin light chain leads to relaxation of smooth muscle
- (Phosphorylated myosin light chain leads to contraction of smooth muscle due to actin myosin cross bridges)
What are nitrates
A class of drugs that, when acted on by mitochondrial enzymes, will break down to generate nitric oxide
What causes NO to be released in endothelial cells
- Acetyl choline, Bradykinin and shear stress stimulate entry of Ca2+ into cell
- Ca2+ stimulates NOS (nitric oxide synthase) to produce NO from L-arg
What is the end diastolic volume (preload) regulated by
sympathetic system and RAAS, (contractility of venules; RAAS (Na+ and H2O retention)
What is heart rate regulated by
sympathetic system and Ca2+
What is contractility regulated by
sympathetic system and Ca2+
What is the total peripheral resistance regulated by
sympathetic system and RAAS
Definition of stable angina
A predictable pattern of pain during exercise that is relieved by rest
What is drug treatment of ischaemic heart disease designed to do
to decrease work done by the heart and/or increase blood supply and treat risk factors.
Give an example of a nitrate
Glyceryl trinitrate (GTN)
Side effects of nitrates
- Postural hypotension
- Headache
- Dizziness
- Reflex tachycardia
How do nitrates increase blood supply to the heart
Nitrates dilate some coronary arteries increasing blood supply to the heart
How do nitrates decrease the heart’s workload
- Nitrates lead to an increase in cGMP
- This leads to a decrease in Ca2+
- Leading to venodilation
- Which decreases preload
- Which reduces the heart’s workload
Why is reflex tachycardia a side effect of nitrates
- Baroreceptors detect low BP in the aortic arch and coronary artery
- Activation of the sympathetic nervous system to release noradrenaline to increase HR and BP
What should you do if treatment with nitrates causes reflex tachycardia
should look to block effects of sympathetic nervous system using a beta blocker, such as bisoprolol.
How do beta blockers decrease cardiac workload
- They decrease the frequency and force of contraction which decreases cardiac output
- Beta blockers also inhibit renin release from kidney and so inhibit RAAS.
Name a beta blocker
Bisoprolol
Side effects of beta blockers
- Bronchoconstriction
- Fatigue
- Contraindicated in patients with peripheral vascular disease
What can mixtures of calcium channel blockers and beta blockers cause
- severe bradycardia
- MI
How do calcium channel blockers decrease cardiac workload
- Decrease the frequency of contraction
- Decrease the force of contraction
- Increase dilation of arterioles
- All of which help to decrease cardiac workload
Which classes of calcium channel blockers decrease the frequency and force of contraction
Phenylalkylamines and benzothiazepines
Which class of calcium channel blockers increase dilation of arterioles
Dihydropyridines
When are calcium channel blockers used to treat ischaemic heart disease
In asthmatics or other groups where beta blockers are contraindicated
Name a dihydropyridine calcium channel blocker
amlodipine
Name a phenylalkylamine calcium channel blocker
verapamil
Name a benzothiazepine calcium channel blocker
Diltiazem
How do calcium channel blockers decrease HR
- CCBs can reduce heart beat by blocking L-type channels in the SA and AV-nodes.
- This will slow the rate of depolarisation and therefore reduce the rate of action potential generation.
How do calcium channel blockers decrease the force of contraction of ventricles
They also decrease the force of contraction of the ventricles by reducing calcium entry through L-type channels.
What are the drugs/classes of drugs used to treat ischaemic heart disease
- Nitrates
- Beta blockers
- Calcium channel blockers
- Ivabradine
- Long acting nitrates (isosorbide mononitrate)
- Nicorandil
- Ranolazine
What does ivabradine do
- Blocks the pacemaker current (Ih/f) in the nodal tissue of the heart.
- Ivabradine will reduce Na+ entry through If channels and so slow the rate of depolarisation of the SA node cells and reduce firing frequency and therefore heart rate.
- It will not directly alter the force of contraction of the heart
Side effects of ivabradine
- Luminous phenomena (Ih) in retina
- Blurred vision
- Dizziness
Name a long acting nitrate
isosorbide mononitrate
What do long acting nitrates do
decrease preload
What does Nicorandil do
It has a dual action:
- It works like nitrates
- And also opens K+ ATP channels. This causes coronary vessels to dilate leading to increase coronary blood flow and dilates arterioles leading to decreased afterload
What does Ranolazine do
Blocks the late Na+ current in the heart that becomes overexpressed in pathological conditions
