Drug Treatment of Angina Pectoris Flashcards
What angina pectoris?
Chest pain due to myocardial ischaemia
Build up of metabolites (adenosine, CO2, lactate, K+ ions) activates sensory nerves
Not a disease itself
What is the ischaemia due to?
Increase myocardial O2 demand which is not met
What are the 3 types of angina?
Stable angina (most common) Unstable angina Variant angina (least common)
What is stable angina?
Attacks predictable, e.g. exercise, stress
Myocardial O2 demand not met
Involvement of chronic occlusive coronary artery disease, i.e. atherosclerosis (use of cholesterol-lowering drugs-stains)
What is unstable angina?
Attacks unpredictable
Coronary artery occlusion due to platelet adhesion to ruptured atherosclerotic plaque (use of anti-platelet drugs)
What is variant angina?
Attacks unpredictable
Coronary artery occlusion by vasospasm
What is dangerous in stable and unstable angina?
May cause coronary steal (where dilation can occur, this sends more blood to already well perfused areas, but where dilatation cannot occur, less blood is delivered because of the fall in input pressure)
What is the difference in stable and variant angina?
Stable- occulusion
Variant- spasm
What occurs in all forms of angina?
Decreased myocardial O2
How can you reduce myocardial O2 demand?
By drugs acting directly on the heart
E.g. B1-adrenoceptor blockers
What are B1-adrenoceptor blockers?
Competitive reversible antagonists of adrenaline and noradrenaline at cardiac beta1-adrenoceptor
What do B1-adrenoceptors do?
Decreases heart rate and force→ decreases myocardial work
Decrease myocardial O2 demand
What types of angina are B1-adrenoceptors used?
All form
What are the adverse effects of beta-adrenoceptor blockers in angina?
Exacerbate asthma (block of beta2-adrenoceptors in bronchi- avoid by use of alternative drug class)
Intolerance to exercise
Hyoglycaemia
Blockade of beta-adrenoceptors may uncover alpha1-mediated constriction in coronaries
What does Ivabradine do?
Blocks If (Na+) current that contributes to SA node depolarisation towards threshold
Sinoatrial node (where heart beat begins)
Decreases heart rate but not force
Decreases myocardial O2 demand
What are vasodilator drugs aiming to do to reduce myocardial O2 demand?
Dilatation of arteries
Dilatation of veins
Venous dilatation
How do vasodilator drugs dilate arteries?
Decreases after-load (force against which left ventricle contracts)
Decreases myocardial work
Decreases myocardial O2 demand
How do vasodilator drugs dilate veins?
Decreases pre-load (diastolic pressure that distends the relaxed left ventricle)
How do vasodilator drugs cause venous dilatation?
Decreases venous return Decreases pre-load Decreases stretch of ventricle and atria Decreases strength of contraction Decreases myocardial work Decreases myocardial O2 demand
What is the Starling mechanism?
More blood, more contraction
Stretch heart further stronger contraction
What is the Bainbridge (atrial) reflex?
A sympathetic reflex initiated by increased blood in the atria
What does the bainbridge reflex cause stimulation of?
SA node
Stimulates baroreceptors in the atria causing increases SNS stimulation
What are nitrovasodilators?
Most commonly used anti-anginals
E.g. GTN, amyl nitrite, isosobide dinitrate, isosobide mononitrate
What is GTN (nitroglycerine, 10% in inert lactose base)?
Taken as sub-lingual tablet or spray
Not orally active (destroyed by first-pass metabolism)
How is Amyl nitrate (volatile liquid) taken?
Vials opened and inhaled
Not now used clinically but has become drug of abuse (poppers)
Both drugs rapid in onset, but action short-lived
What are the uses of nitrovasodilators?
Prophylaxis in stable angina (i.e. taken immediately before exercise)
Rapid relief of ongoing angina attack (all forms)
How are isosobide dinitrate and isosobide mononitrate taken?
Taken orally
Slower in onset and more prolonged in duration than GTN
Used for sustained prophylaxis in all forms of angina
What are all nitrovasodilators?
Pro drugs
What are nitrovasodilators?
Lipophilic- readily enter smooth muscle cells and are reduced to nitric oxide
What are nitrovasodilators termed?
“NO donors”
What do nitrovasodilators mimic?
Action of endothelium- derived NO
What does nitric oxide activate?
Soluble guanylate cyclase (sGC)
Cytoplasmic (soluble) enzyme
What does the receptor on soluble guanylate cyclase contain?
A ferrous (Fe2+) haem moiety (like O2 binding site of haemoglobin)
What does NO bind to?
Haem receptors
What does the binding of NO to haem receptors cause?
Enzyme activation
Converts GTP to cGMP
Increased cGMP causes vasodilation
What are anti anginal actions of nitrovasodilators?
Venous dilatation > arterial dilatation
What are the side effects of nitrovasodilators?
Headache (dilataton of cerebral arteries)
Tolerance on prolonged use- need drug free “washout” period to restore efficacy
When do L-type voltage operated calcium channels open?
Upon membrane depolarisation
Where does calcium enter in L-type voltage operated calcium channels?
Cardiac and vascular smooth muscle
What is the mechanism of L-type channel block?
Open channel block
Allosteric modulation
Tissue selectivity
What drugs use the open channel block mechanism?
Verapamil and diltiazem work this way
What is allosteric modulation?
Bind at allosteric site and reduce channel opening
Nifedipine work this way
What is tissue selectivity?
Smooth muscle: nifedipine > dilitiazem > verapamil
Cardiac muscle: verapamil > dilitiazem > nifedipine
What is the anti-anginal action of L-type blockers?
Dilate arteries (little effect on veins) Decreases heart rate and decreases force
What does the dilation of arteries by L-type blockers cause?
Decreases after-load
Decreases myocardial O2 demand
What does the decrease in heart rate and force by L-type blockers cause?
Decreases myocardial O2 demand
What types of angina can L-type blockers be used in?
All forms
What is dilatation of coronary arteries useful for? And what it is harmful in?
Valuable in variant angina (vasospasm)
Dangerous and may cause coronary steel in stable unstable angina
What is vasospasm?
A condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis).
What is a coronary steel?
Where an alteration of circulation patterns lead to a reduction in the blood directed to the coronary circulation.
What does Nifedipine cause?
Coronary steal in 10% of patients
What are other uses of L-type blockers?
Anti-hypertensive agents (decreases TPR; Decreases HR and decreases SV→ decrease in CO
Anti-dysrhythmic agents (Class IV)
What are adverse actions of L-type blockers?
Coronary steal
Headache
Constipation
What can occur in an extreme overdose of L-type blockers?
Heart block
Cardiac failure
What are the steps following the diagnosis of stable angina?
- Short-acting nitrovasodilator (GTN) plus Beta blocker or calcium channel blocker plus drugs for secondary prevention (antiplatelet, lipid-lowering, or anti-hypertensive drugs, as appropriate)
- Combine beta blockers and calcium channel blockers
- Consider adding long-acting nitrovasodilator or ivabradine
- Consider surgical intervention: stenting or coronary artery bypass grafting
