Flashcards in L38. Drugs for Ischaemic Heart Disease Deck (37):
What are the only 2 ways to increase flow to the coronary arteries to the heart?
1. Dilation of coronary arteries
2. Decreasing heart rate (increase time in diastole = increased patent time of the coronary vessels = increased time for perfusion)
What does the demand for oxygen of the heart depend on?
Demand depends on the Work of the heart
What does the work of the heart depend on? [3 factors]
1. CO = HR x SV
2. Preload (venous return)
3. Afterload (resistance of the arteries and TPR)
What is the cause of Angina Pectoris in Ischaemic Heart Disease?
An IMBALANCE between supply and demand where there is insufficient oxygen perfusion to meet demand.
There is a consequent release of chemical mediators (eg. adenosine) which leads to pain
What are the three types of angina? Describe each one
1. Stable (classic) angina
Pain upon exertion or stress associated with coronary artery disease
2. Variant (vasospastic/Prinzmetal's) angina
Unpredictable coronary vasospasms at rest with an unknown mediator (the aim is to find the trigger then remove it)
3. Unstable (cresendo, at rest) angina
With either rest or effort where pain builds up and manifests. It holds the potential for thrombi formation, occlusion and MI
What is the difference between the healthy heart and the atherosclerotic heart that leads to stable angina?
With a normal heart, exertion leads to an increased workload (increased demand), the arteries dilates and allows more blood flow and arteriole vasodilation to allow for incresed oxygen.
With an atherosclerotic heart the vessels are stiff at rest and have intrinsic narrowing (plaque) and at rest the arterioles are ALREADY DILATED to compensate for these. Thus upon exertion there isn't much the vessels can do because artery dilation is limited by stiffness and arterioles are already dilated.
What is the treatment for stable angina?
Prevention of attacks
Prevent progression to a heart attack
What are the two main aims of treatment of stable angina?
1. Increase the Supply
2. Reduce the Demand
What are the pharmacological ways to increase supply to the heart?
Dilation of the coronary arteries
Reduce the heart rate
What are the pharmacological ways to decrease the demand on the heart?
Reduce preload (dilate the veins, reduce venous return)
Reduce afterload (dilate the arteries and reduce TPR)
Decreasing CO (decrease HR and/or SV)
What are the majority of drugs for stable angina used for?
What are the major drugs used for modulating preload, CO and afterload?
Cardiac Output: Calcium channel blockers, beta blockers, ivabradine
Afterload: Ca channel blockers
What are the Nitrates?
They mimic endogenous production of nitric oxides and lead to vascular relaxation
What is the mechanism of action of nitrates?
Prodrug that undergoes biotransformation in the body
NO stimulates guanylate cyclase in vascular smooth muscle
GTP is converted to cGMP
cGMP leads to dephophorylation of the myosin light chain
This STOPS cross bridge formation and stabilises the relaxed form
Where does the action of Nitrates mainly affect?
Affects ALL VESSELS
Has a larger effect on the veins (to reduce preload) and a less on the arteries.
It doesn't affect the flow in coronary vessels
What is an example of a short acting nitrate? How is it administered, why and when?
GLYCERYL TRINITRATE (GTN)
Given sublingually (because it is prone to first pass metabolism into inactive metabolite) for an acute attack of angina in anticipation for an MI following.
Can also be given transdermally for prophylaxis
May be given IV for an emergency
Why does care need to be taken with the storage of glyceryl trinitrate?
It is absorbed by plastic, unstable and sensitive to light
What is an example of a long acting nitrate? How is it administered, why and when?
Also subject to first pass metabolism but this is into an ACTIVE metabolite
Thus is given orally in anticipation of effort (prophylaxis)
What are some adverse effects of isosorbide dinitrate?
- Can affect other smooth muscles (gut and airways) - not clinically significant
- Postural hypotension (due to too much vasodilation)
- Reflex tachycardia (usually used in combination with beta blockers or cardiac selective Ca channel blockers)
- Headache, flushing (due to cerebral, head and neck dilation)
- Drug-drug interactions: can cause massive drop in pressure
What is a major contraindication for use of nitrates?
Phosphodiesterase inhibitors (eg. viagra) because they also reduce the pressure - leading to too much hypotension
What is tolerance?
When there is a reduced effectiveness of the drug with continuous usage and there is a need to take higher concentrations of the drug to get the same effect.
What is the mechanism of tolerance for nitrates?
Likely to be a combination of a few things:
- Classic: In order to Nitric Oxide to be produced and released, tissue thiols need to be depleted (N-acyl cysteine restores GTN effect)
- Increased release/sensitivity to constrictors to counteract the dilation
- Increased production of free radicals by endothelial cells: scavenge NO (reduces bioavailability)
- Reduced or abnormal muscle mitochondrial ALDH2, decreasing NO production and increases free radicals
What is a drug free period? Why is it important?
A time where the drug isn't used (eg. overnight removal of patches) to reduce the occurance of tolerance
The affect of calcium channel blockers depends on...
The selectivity of the drug (different calcium receptors - vasculature vs. cardiac)
Why must non-selective drugs be used for heart failure?
Because they affect both vascular and cardiac calcium channels. Thus reduces contractile ability of the heart (exacerbates cardiac failure)
What is the mechanism of action of calcium channel blockers?
Block Calcium entry into the heart through L-type channels leading to decreased heart rate and contraction.
VASCULATURE: (also used in hypertension)
Through blockage of voltage L-type and receptor channels leading to arterial dilation
What are examples of the different types of the Ca channel blockers?
Cardiac: Verapamil, diltiazem
Vessel: dyhydropyridines: nifedipine and delodipin
What are some adverse affects of the calcium channel blockers?
Verapamil: flushing, headache, oedema, bradycardia, AV block (should never be taken with Beta blocker (cardiodepressive))
Nifedipine: Flushing, headache, oedema, hypotension, reflex tachycardia
What are the beta blockers? Give examples
Block the effects of the sympathetic nervous system on cardiac B1 adrenoreceptors
First line therapy for prophylaxis - atenolol (cardio selective) and propanolol (non-selective)
What is important to note about the treatments for angina?
They are symptomatic relief and don't treat the underlying problem or change the risk
How are these drugs usually used?
Most of the time, there is COMBINATION THERAPY to reduce frequency of use, maximise effect and minimise adverse effects
What is Ivabradine?
A novel therapy that causes a pure reduction in HR (ie. doesn't affect contractility) by specifically inhibiting the inward sodium/potassium (If) current in the SA node and thus decreases diastolic depolarisation (takes longer to reach threshold)
What is interesting about this therapy?
Shown to reduce the risk of MI (modifies the disease)
What are some adverse effects of ivabradine?
Brightness in the visual field (retinal effects)
Increased levels by anti-fungals and antibiotics
How is variant angina treated?
Relieve coronary spasms by short acting nitrates
Prophylaxis with dihydropyridines and Ca channel blockers in combination
Beta-adrenoreceptors are CONTRAINDICATED because a vasospasm that occurs via the adrenoreceptor may be made worse by a dilated vessel
What are the treatments of unstable angina?
Same as classic/stable angina
But also INCLUDES aspirin to prevent thrombosis occuring