Clinical pharmacology of stable coronary artery disease Flashcards
Features of ischaemic heart disease
- It is the most common cause of death in pre-retirement males
- Acute coronary syndromes
- Stable coronary disease
Acute coronary syndromes
- Myocardial syndromes: STEMI or NSTEMI
- Unstable angina pectoris
Stable coronary artery disease examples
- Angina pectoris
- Silent ischaemia
Risk factors of ischaemic heart disease
- Hypertension
- Smoking
- Hyperlipidaemia
- Being male
- Post-menopausal females
Features of Stable coronary artery disease
- SCAD arises as a result of a mismatch between myocardial blood/oxygen supply and demand
- Attacks of angina (chest pain) may be precipitated by any stress which increases cardiac work and myocardial oxygen demand
- Anything which increases heart rate, stroke volume or blood pressure
What are determinants of demand ischaemia (ischaemia during stress)?
- Heart rate
- Systolic blood pressure
- Myocardial wall stress
- Myocardial contractility
What are determinants of supply ischaemia (ischaemia at rest)?
- Coronary artery diameter and tone
- Collateral blood flow
- Perfusion pressure
- Heart rate (duration of diastole)
Features of Hyperlipidaemia
- Atherosclerosis at the start
- Disease of the muscular arteries (not veins)
- Progressive deposition of cholesterol esters
- Accounts indirectly for half of annual mortality
- Lesions start as fatty streaks (aged 20)
- Fibrous plaque
- Most of the changes are in the intimal layer
- Most of the foam cells are of smooth muscle origin
- Necrotic core
- Fibrous cap
How can drugs help to correct imbalance?
- Decreasing myocardial oxygen demand by reducing cardiac workload:
Reduce heart rate
Reduce myocardial contractility
Reduce afterload - Increasing the supply of oxygen to ischaemic myocardium
What is the purpose of drug treatment?
- Relieve symptoms
- Halt the disease process
- Regression of the disease process
- Prevent myocardial infarction
- Prevent death
Definition of stable angina
A clinical syndrome of predictable chest pain or pressure precipitated by activities such as exercise or emotional stress, which increase myocardial oxygen demand
Types of drugs used in drug therapy of angina
- Rate limiting
- Vasodilators
- Anti-platelet
- Potassium channel openers
- Cholesterol lowering agents
Rate limiting drugs used in drug therapy
- Beta-adrenoreceptor antagonists
- Ivabradine
- Calcium channel blockers
Vasodilators used in drug therapy
- Calcium channel blockers: reduce afterload on the heart
- Nitrates e.g. GTN: oral, sublingual
What is the main potassium channel opener used in angina?
Nicorandil
Nitrates used in angina
- Short duration: sublingual nitroglycerin
- Intermediate: oral nitroglycerin
- Long duration: transdermal nitroglycerin
Anti-platelet drugs used in angina
- Aspirin
- Clopidogrel
- Tigagrelor
Cholesterol lowering agents used in angina
- HMG CoA reductase inhibitors
- Fibrates
Beta blockers used in angina and features
Bisoprolol, Atenolol
- Beta blockers are reversible antagonists of the Beta1 and Beta2 receptors
- Newer drugs are cardioselective acting primarily on the beta1 receptors
- Block the sympathetic system
What do beta blockers actually do?
- Decrease three major determinants of myocardial oxygen demand: heart rate, contractility, systolic wall tension
- Also allow improved perfusion of the subendocardium by increasing diastolic perfusion time
- Decrease the force of myocardial contraction
- Decrease the cardiac output
- Decrease the velocity of contraction
- Decrease blood pressure
- Protect cardiomyocytes from oxygen free radicals formed during ischaemic episodes
What is the rebound phenomena of beta blockers?
- Sudden cessation of beta blocker therapy may precipitate myocardial infarction
- Those at risk include patients with angina and men over 50 years receiving beta blockers for other reasons
Contraindications of beta blockers
- Asthma
- Peripheral vascular disease
- Raynauds syndrome
- Heart failure: those patients that are dependent on sympathetic drive
- Bradycardia/Heart block
Adverse drug reactions of beta blockers
- Tiredness/fatigue
- Lethargy
- Impotence
- Bradycardia
- Bronchospasm
- Rebound: sudden cessation of beta blocker may precipitate MI
Features of Drug-Drug interactions
Primarily Pharmacodynamic:
- Hypotension when used with other hypotensive agents
- Bradycardia when used with other rate limiting drugs such as verapamil or diltiazem
- Cardiac failure when used with negatively inotropic agents such as verapamil, diltiazem or disopyramide
- NSAIDs antagonise antihypertensive actions
Exaggerate and mask hypoglycaemic actions of insulin or oral hypoglycaemics
Examples of Calcium channel blockers for angina
- Diltiazem
- Verapamil
- Amlodipine
Features of calcium channel blockers
- Prevent calcium influx into myocytes and smooth muscle lining arteries and arterioles by blocking the L-type calcium channel.
- Rate limiting CCB’s like diltiazem and verapamil also reduce heart rate and force of contraction
- Vasodilating CCBs like nifedipine or amlodipine may produce a reflex tachycardia
Further features of CCBs
- CCBs reduce vascular tone and produce vasodilatation and reduce afterload: reduce myocardial work load
- Rate limiting CCBs reduce the heart rate and the force of myocardial contractility: reduce myocardial oxygen requirements
- CCBs may also produce coronary vasodilatation but of little importance
Contraindications of CCBs (Nifedipine)
- Never use nifedipine immediate release
- Evidence that the use of rapidly acting vasodilatatory-CCBs (nifedipine) may precipitate acute MI or stroke
- Post MI: may increase morbidity and mortality in patients with impaired LV function
- Unstable angina: evidence that dihydropyridines may increase infarction rate and death in the unstable patient
Adverse drug reactions of CCBs
- Ankle oedema: affects 15-20% of patients and does not respond to diuretics
- Headache
- Flushing
- Palpitation
Examples of Nitrovasodilators for angina
- Glyceryl trinitrate (GTN): sublingual, buccal, transdermal
- Isosorbide mononitrate: sustained release formulation, tablets
- Isosorbide dinitrate: sustained release formulation, tablets
Why is GTN administered sublingually?
Triglyceryl trinitrate undergoes high first pass metabolism in liver so the drug will be broken down and not work if given orally
- So, sublingual administration bypasses this portal circulation and GTN can directly act on Large vessels
Pharmacology of nitrovasodilators
- Nitrovasodilators relax almost all smooth muscle by releasing NO which then stimulates the release of cGMP which produces smooth muscle relaxation.
- Reduce preload and afterload so reduce myocardial oxygen consumption.
How do nitrates relieve angina?
- Arteriolar dilatation and so reducing cardiac afterload and thus myocardial work and oxygen demand
- Peripheral venodilatation and so reducing venous return, cardiac preload and thus myocardial workload
- Relieving coronary vasospasm
- Redistributing myocardial blood flow to ischaemic areas of the myocardium
- No evidence that nitrates reduce mortality
What are the uses of GTN?
- Used for rapid treatment of angina pain
- To avoid first pass metabolism is given by the sublingual route
- May be used frequently and prophylactically
What are the uses of oral nitrates?
- Commonly given as a once a day sustained release formulation
- Used for prophylaxis
What are the uses of intravenous nitrates?
The main stay in the treatment of unstable angina where they are used in combination with heparin
Tolerance to nitrate therapy and how do you overcome it?
- Tolerance to the effects nitrate therapy can develop rapidly.
Overcome this problem by:
- Giving asymmetric doses of nitrate 8am and 2pm
- Using a sustained release preparation which incorporates a “nitrate free period”
Adverse drug reactions of nitrate therapy
- Headache: increase dose slowly
- Hypotension: GTN syncope
What are new approaches to myocardial ischaemia?
- Metabolic modulation (trimetazidine)
- Sinus node inhibition (ivabradine)
- Late Na+ current inhibition (ranolazine)
- Preconditioning (nicorandil)
Action of Nicorandil - IPC
- Activate “ATP sensitive potassium channels”
- The entry of potassium into cardiac myocytes inhibits calcium influx and so has a negative inotropic action.
Preconditioning: Nicorandil
Activation of ATP-sensitive K+ channels:
- Ischaemic preconditioning
- Dilation of coronary resistance arterioles
Nitrate-associated effects:
- Vasodilation of coronary epicardial arteries
What is the nitrate moiety of Nicorandil
The nitrate moiety produces relaxation of vascular smooth muscle with dilation of systemic venous circulation and epicardial coronary arteries
Features of Ivabradine
- It is a sinus node If channel inhibitor
- Slows the diastolic depolarisation slope of the SA-node
- Results in a reduction in heart rate: reduces heart rate and myocardial oxygen demand.
What does Ivabradine reduce?
- It reduces primary end point in angina patients
- It reduces myocardial infarction in patients with angina
Features of Ranolazine
- Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle in a variety of voltage gated sodium channels.
- Inhibiting that current leads to reductions in intracellular calcium levels.
- This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle.
Antiplatelet agents and features
- Low dose Aspirin (75-150mg)
- The formation of platelet aggregates are important in the pathogenesis of angina, unstable angina and acute MI.
- Aspirin is a potent inhibitor of platelet thromboxane production.
- Thromboxane stimulates platelet aggregation and vasoconstriction.
What can the regular daily use of aspirin do?
- In acute MI: reduce mortality by 23%, in combination with streptokinase reduce mortality by 42% and reinfarction by 52%.
- In unstable angina: reduce MI and death by 50%.
- In secondary prevention: reduce reinfarction by 32% and combined vascular events by 25%.
Features of Clopidogrel
- Inhibits ADP receptor activated platelet aggregation.
- Prevention of atherosclerotic events in PVD.
- Acute coronary syndrome
- Same incidence of bleeding as aspirin but possibly lower GI bleeding!
- Newer agents such as prasugrel and ticagrelor. Possible advantages.
Examples of Cholesterol lowering agents
- Simvastatin
- Pravastatin
- Atorvastatin
Features of cholesterol lowering agents
- These are HMG CoA Reductase inhibitors which are the most effective cholesterol lowering agents.
- Studies have demonstrated that aggressive cholesterol lowering post MI can reduce cardiovascular mortality by 42% and total mortality by 30%.
What is the NICE guidance treatment regimen?
- Beta blockers should be used for the relief of symptoms of stable angina.
- When adequate control of anginal symptoms is not achieved with beta-blockade a calcium channel blocker should be added.
- If the person’s symptoms are not satisfactorily controlled consider either switching to the other option or using a combination of the two.
What should all patients with stable angina receive?
- All patients with stable angina should be considered for treatment with ACEi.
Drugs for secondary prevention of cardiovascular disease?
- Aspirin 75mg daily taking into account the risk of bleeding and comorbidities.
- ACE inhibitors for people with stable angina and diabetes.
- Statin treatment
- Treatment for high blood pressure
