Angina pectoris is due to insufficient coronary blood supply to the Myocardial muscle.
The symptoms are severe chest pain over the heart
Occurrence of chest pain is due to an imbalance between oxygen supply and oxygen demand
Angina attacks are seen whenever there is slightest increased physical work
Oxygen demand is directly related to heart rate, strength of contraction and resistance to blood flow
In angina , the diminished blood supply to heart does not cause irreversible changes related to obstruction or narrowing of coronary arteries as occur in atherosclerosis , arterial spasm, pulmonary hypertension
There are three types of angina pectoris
Stable angina
It is effort induced pain from physical activity or emotional stress
This pain is relieved by rest and is usually predictable and reproducible
Unstable angina
It is pain that occurs with increasing frequency that diminishes the patients ability to work and decreases response t o treatment. It may signal on coming MI
Variant angina
It is pain due to coronary artery spasm
The ST segment is elevated and prolonged during pain.
This pain may occur at certain times of the day, but is not stress-induced
Symptoms
Severe Chest Discomfort which may be described as heaviness pressure, tightness, choking , a squeezing sensation or a combination of these
Other symptoms are sweating , dizziness and dyspnea
Diagnosis
Diagnosis made from the physical examination , resting and exercise ECG, coronary angiogram. and radioisotope study
The ECG may be normal but usually the T wave is flat or inverted
Risk factors
Hypertension
Increased serum lipoprotein levels
Smoking
Increased Serum Glucose Levels
Advanced age
Coronary artery disease
Obesity
Management of angina
To treat attack of angina
To reduce oxygen demand of heart by reducing preload or after load
To prevent complications like MI
To improve exercise tolerance
Non- pharmacological measures
1. Explaining eh patient about nature of the disease and altering life style
2. Avoiding smoking, alcohol, stress
3. Cardio protective diet and exercises
Pharmacological measures
The treatment for angina pectoris involves either to increase the oxygen supply to the sub endocardium or to reduce the demand for oxygen so that myocardium adjust to the available oxygen supply or by using both mechanisms
The oxygen supply to the heart muscle can be increased by giving coronary dilatory drugs or the demand for oxygen can be reduced by depressing the activity of the heart by giving but a adrenergic receptor blocking agents
The drugs used angina pectoris is known as anti-anginal drugs
Classification
1. Nitrates
Nitroglycerin, isosobide dinitrate, isosobide mononitratee
2. Beta- blockers
Propranolol, atenolol
3. Calcium channel blockers
Verapamil, diltiazem, amiodipine, nifedipine
4. Potassium channel openers
Nicorandil, pinacidil
5. Miscellaneous
Dipyridamone, asprin, trimetazidine
1. Nitrates
Nitric oxide is a natural vasodilator in human body
It is produced by endothelial cells and is responsible mainly for dilation of veins
To some extent it also dilates arteries
Basically nitrates are used in explosives
Tablets , if are exposed to heart or air, lose their potency due to evaporation
These are drugs of choice in angina pectoris
Mechanism of action
Nitrates act in body by releasing NO
Nitrates are vasodilators
They are converted to NO which activates vascular guanylyl cyclase which in turn increases the synthesis of cGMP
This cGMP brings about on phosphorylation of protein kinases (prevents interaction of actin with myosin)
It also reduces free systolic calcium by preventing calcium release from sarcoplasmic reticulum and by increasing calcium efflux
These effects result in relaxation of smooth muscles
It causes vasodilatation are also relaxation of other smooth muscles
Nitrates ----- Denitration --- Release of NO ---- reduced activation of guanylyl cyclase
- Increase in intracellular cyclic GMP ----- dephosphorylation of myosin light chain
Kinase ----- reduced activation of myosin ----- reduced actin myosin coupling----
Reduced contraction of smooth muscles --- relaxation of smooth muscles
Pharmacokinetics
Nitrates are available for oral, sublingual, parenteral use and as ointment and transdermal patches for topical use
Nitrates usually has good absorption from skin and GIT
All nitrates have good lipid solubility
Problem with oral administration is first pass effect
Hence for rapid action they are administered by sublingual route and the action starts within 1 minute
One more advantage with sublingual administration is that in case of signs of overdose the tablet can be thrown out or can be swallowed
Swallowing will not produce the effect immediately and the magnitude of effect will also be less due to first pass effect
Topical preparations are used for the prevention of nocturnal episodes of angina
But there is an increased risk of development of tolerance with topical and slow release preparations
Pharmacological actions
Nitrates are predominantly vasodilators
Venodilation reduces venous return to the heart thereby reducing preload
Arteriolar dilation reduces vascular resistance thus decreasing after load
As both preload and after load are reduced, work load of the heart is decreasing thereby reducing oxygen requirement of the heart
Nitrates also brings about some coronary vasodilation
But , the beneficial effect in stable angina is due to its vasodilator properties
In variant angina, nitrates relieve vasospasm due to coronary vasodilation
Nitrates also cause dilation of blood vessels in the skin- resulting In flushing, dilatation of the meningeal vessels result in headache
Bronchial smooth muscles are also relaxed
Nitrates also inhibit platelet aggregation but the therapeutic benefit from this is yet to be established
Adverse effects
Headache common, flushing , sweating , Palpitation, weakness, rashes can occur
Tolerance develops on repeated long term use, so tolerance can be avoided
Tolerance can also be minimized by twice or thrice daily dosing schedule
Nitrates are said to cause a sort of dependence
Drug interactions
Nitrates and sildenafil
Sildenafil(Viagra), a drug used in erective dysfunction is a phosphosdiesterase inhibitor
It increases cGMP activity resulting in relaxation of cavemosal as well as vascular smooth muscles. Vasodilatation results in hypotension
Sildenafil potentiates the action of nitrates and together can cause severe hypotension
Deaths have been reported due to myocardial infarction
Nitrates produce hypotension if are taken along with other vasodilators or with alcohol
Nitrates are used with caution in hepatic and renal impairment
Dry mouth reduces absorption of sublingual nitrate
Dose & route
Drug | Dose & route | Duration of action |
Nitroglycerin | 0.5 mg SL 5 mg ORAL 2%skin ointment applied 1-2 inches on the pericardial region | 15 – 40 min 4-8hr
4-6 hrs |
Isosorbide dinitrate
| 5-10 mg SL 10-20 mg oral | 20 – 40min 2-3 hrs |
Isosorbide mononitrate | 10-20mg oral | 6 – 8 hrs |
11 . Beta- blockers
These reduce the frequency an severity of attacks of angina and are useful in the prevention of angina
Exercise, emotion and similar situations increase sympathetic activity leading t o increased heart –rate , force of contraction and BP, thereby increasing oxygen consumption by the heart
Beta blocker prevent angina by blocking all these action and thereby prevent an increase in myocardial oxygen demand
The beta- blockers blocking beta receptors on heart, reduce rate and contractibility of heart and reduce work load and oxygen demand of heart
B – blockers improve myocardial perfusion by increasing diastole
But they can increase coronary spasm in variant angina
Cardio selective agents usually are preferred in angina
They are used for the long term prophylaxis of classical angina and may be combined with nitrates
They can increase coronary spasm on variant angina . They are not useful in variant angina
Propranolol is used for prophylactic treatment of the anginas
Metoprolol
Dose
50 – 100 mg daily given as single or divided doses
Atenolol
Dose
50 – 100 mg daily given as single or divided doses
Maximum dose – 200 mg daily
111. Calcium channel blockers
S No | CCB | Dose | Route |
1 | Verapamil | 40-120mg 2.5 mg | Orally 8 hourly IV
|
2 | Diltiazem | 30 – 60 mg 20 mg | Orally 8 hourly IV
|
3 | Nifedipine | 5- 20 mg | Orally 8 hourly
|
4 | Nimodipine | 30 -60 MG | Orally 4 hourly
|
5 | Nisoldipine | 20 -40 mg | Orally once daily
|
6 | Nicardipine | 20 -40 mg | Orally 8 hourly
|
7 | Nitrendipine | 5 -20 mg | Orally once daily
|
8 | Amlodipine | 5- 10 mg | Orally once daily
|
9 | Felodipine | 5- 10 mg | Orally once daily
|
10 | Isradipine | 2.5 mg | Orally 12 hourly
|
Discovery of calcium channel in the cardiac myocytes helped in understanding the mechanisms involved in smooth muscle contraction
Verapamil was the first agent found to have calcium channel blocking properties
These act by interfering the calcium entry into the cardiac muscle, cardiac contractility is depends on the concentration of eh calcium , these drugs will decrease the availability of the calcium to the cardiac cell, anti-angial effects due to improvement in coronary blood flow, decrease in systemic vascular resistance and BP this decrease oxygen demand of heart
Mechanism of action
The depolarization of the cardiac and vascular smooth muscle cells depend on the entry of extra cellular calcium into the cell through the calcium channels
Intracellular calcium is the increased by receptor – mediated action , that is agonist induced calcium release – mediated to the second messenger IP3
This calcium trigger the release of intracellular calcium from the sarcoplasmic reticulum
All these calcium ions bring about contraction of the cardiac and vascular smooth muscle cells
Calcium channel antagonists inhibit the entry of calcium by blocking the L- type of calcium channels
There are 3 types of calcium channels - L, N and T types
This decreases calcium current and calcium entry into cardiac and vascular smooth muscle
Actions
1. Heart
CCBs depress myocardial contractility, reduce heart rate and in higher doses they slow AV conduction
They reduce cardiac work and thereby myocardial oxygen consumption
Verapamil, bepridil and diltiazem have prominent cardiac effects
2. Coronary circulation
CCBs dilate the coronary vessels, increasing the coronary blood flow
Hence they are useful in variant angina
3. Vascular smooth mussels
Relaxation of the arteriolar smooth muscles results in reduced peripheral vascular resistance and blood pressure
The effect on venous beds is not significant
Drug interactions
Verapamil and diltiazem should be avoided in patients receiving beta- adrenergic blockers because
Verapamil has prominent myocardial depressant actions. AV conduction of depressed and usually bradycardia is seen . Hence it should not be combined with B- blockers
Verapamil can precipitate digoxin toxicity by increasing digoxin levels
Adverse effects
Verapamil and diltiazem produce constipation , bradycardia, heart block, hypotension and skin rashes
They may precipitate CCF in patients with diseased heart long term use of CCB s can cause gum hyperplasia
1V . Potassium channel openers
Since intracellular concentration of K is much higher compared to extra cellular region, potassium opening results in outflows of potassium ions and hyperpolarisation
It is used to treat angina pectoris, hypertension , CHF, alopecia etc
Nicorandil
It is an arterial and venous dilator
Opening of the ATP-sensitive K channels results in efflux of K leading to hyper polarization and therefore relaxation of the vascular smooth muscles
In addition it also acts through metric oxide like nitrates
Nicorandil is tried in angina when other drugs do not afford significant benefit
It is expensive
Interactions
Hypertensive interaction may occur with alcohol TCAs and other vasodilators
Adverse effects
Headache , flushing , palpitation, dizziness, vomiting and hypotension
Dose
10 – 30 mg twice daily or maximum dose 30 mg
Pinacidil
It is similar to nicorandil
It is also useful in hypertension
V. Miscellaneous
Dipyridamole
It is a coronary vasodilator but it diverts the blood from ischemic zone and is therefore not beneficial
It inhibits platelet aggregation for which it is used in post MI and post – stroke patients for prevention of coronary and cerebral thrombosis
Dose - 200mg bid
Aspirin
Long term administration of low dose aspirin is recommended to prevent myocardial infarction
Aspirin inhibits platelets aggregation and thereby prevents MI I n patients with angina
Dose - 75 mg once a daily
Trimetazidine
It is a calcium channel blocker claimed to have a protective effect on the ischemic myocardium and to maintain left ventricular function
It is tried in exertional angina
Dose – 20 mg
Combination of drugs in angina
1. Nitrates + B – blockers
Very effective in exertional angina
Reflex tachycardia due to nitrates is countered by B- blockers
Ventricular dilation due to B- blockers is opposed by nitrates
2. Nitrates + CCBs
Nitrates decrease preload,
CCBs reduce after load and the combination reduces cardiac work load
3. Nifedipine + B- blockers
The antiangial effects are additive
Reflex tachycardia due to nifedipine is countered by B- blockers
4. Nitrates + B- blockers + CCBs
If the angina is not controlled by 2 drug combinations
3 drugs can be used
Nitrates reduce preload,
CCBs reduce after load
While B- blockers decrease heart rate
This combination is useful in server angina .
