Pharmacology Of Cardiac Disease Flashcards
Define acute coronary syndromes.
A set of cardiovascular conditions wherein blood supply to the heart muscle is suddenly blocked via occlusion of coronary arteries by thrombus.
What symptoms characterise acute coronary syndromes?
Severe chest pain
SOB
What are some specific examples of acute coronary syndromes?
ST-segment elevated myocardial infarction (STEMI)
Non-ST segment elevated (NSTEMI)
Unstable angina
Why is urgent treatment required for acute coronary syndromes?
They are life-threatening
What are the 2 basic principles for the treatment of acute coronary syndromes?
- Increase O2 supply of myocardium: improve coronary blood flow + administer O2
- Reduce O2 demand of myocardium: reduce HR + force of contraction, cardiac preload + afterload
Define heart failure.
Inability of the heart to deliver O2 at a sufficient rate to metabolising tissues throughout the body caused by abnormality of cardiac structure or function.
If hypertension is left untreated, what can occur?
Atherosclerosis which reduces blood flow to heart
Structural abnormalities in the heart e.g. L ventricular hypertrophy
What are the treatment strategies for chronic heart failure?
- Improve contractility with positive ionotropes e.g. sympathomimetics (Dobutamine)
- B-blocker to modulate enhanced/sustained cardiac adrenergic drive
- Reduce oedema with diuretics e.g. loop (Furosemide)
- Reduce preload + afterload e.g. ACEi (Ramipril) or ARB (Losartan)
What are some other important targets, especially for preventing cardiovascular disease?
- Platelets: regulate blood clotting to prevent coronary thrombosis
- Hepatocytes: regulate cholesterol production + uptake by liver reducing atherosclerosis
What are the main blood vessel cells?
- Fibroblasts: connective tissue outer layer
- SMCs: contractile vascular smooth muscle layer
- Endothelial cells: lining of blood vessel lumen
Describe the signal transduction occurring in vascular smooth muscle cells allowing them to contract.
- Angiotensin II binds to its receptor which stimulates IP3
- IP3 mobilises Ca2+ stores in SR
- Ca2+ also comes in through L-type channels on the cell membrane
- Ca2+ binds calmodulin which stimulates MLCK
- MLCK + ATP phosphorylate MLC causing contraction
Describe the signal transduction occurring in vascular smooth muscle cells allowing them to relax.
- NO diffuses through the SMC membrane
- cGMP is stimulated
- cGMP stimulates MLCP
- MLCP dephosphorylates MLC causing relaxation releasing
What do ACE inhibitors do?
Block conversion of angiotensin I to angiotensin II by ACE
What do angiotensin receptor blockers (ARBs) do?
Directly block activation of the angiotensin II receptor
What physiological effect do both ACE inhibitors and ARBs have?
Decreased vasoconstriction in peripheral blood vessels leading to reduced peripheral resistance, reduced cardiac afterload + lowers BP
Aldosterone secretion is reduced leading to less H2O retention, lower plasma volume + lower cardiac preload
What is the key side effect of ACE inhibitors that ARBs do not really cause?
Persistent cough
What is the mechanism of action of calcium channel blockers?
- Prevent opening of voltage-gated L-type Ca2+ channels
- Reduced Ca2+ influx into SMCs
- Vasodilator effect on resistance in vessels decreasing cardiac afterload
- Drive coronary artery dilation + improve blood flow
- Some can affect heart directly with -ve chronotropic + inotropic effects
What are the key side effects of calcium channel blockers?
Ankle-swelling
Palpitations
Do calcium channel blockers act on veins?
Generally not
What are the common calcium channel blockers?
Nifedipine Amlodipine (dihydropyridine subclass)
What are the key examples of nitrate vasodilators?
Glyceryl Trinitrate (GTN) Isosorbide Mononitrate (ISMN)
What is the mechanism of action of nitrate vasodilators?
- Metabolised to release NO
- NO stimulates sGC
- Increased cGMP in vascular SMCs
- Drives dephosphorylation of MLC via activation of MLCP
- Inhibits influx of Ca2+ into SMCs
- Drives vascular SMC relaxation
What is the key side effect of nitrate vasodilators?
Headache
What effects so nitrate vasodilators have on the heart?
Dilates arteries AND veins:
- Venodilation reduces cardiac preload
- Coronary artery vasodilation increases blood + O2 supply to myocardium
- Moderate arteriolar dilation reduces cardiac afterload
Describe the signal transduction in cardiomyocytes causing contraction.
- B1-adrenoceptor stimulation
- G proteins activate AC
- AC converts ATP to cAMP
- cAMP stimulates PKA
- PKA increases free Ca2+ levels inside cell via activation of channels on membrane + release from SR
- Ca2+ causing contraction
What is the mechanism of action of beta-blockers?
- Competitive inhibitors of A + NA at B-adrenoceptor sites inhibiting sympathetic stimulation of heart muscle
- -ve chronotropes + inotropes so decrease HR + cardiomyocyte contractility
- Reduce workload of the heart relieving O2 demand
What types of beta-blockers are selective for the heart?
B1-antagonists e.g. Atenolol
What are the key side effects of beta-blockers?
Dizziness
Constipation
What do diuretics do?
Act in kidney on renal tubular epithelial cells to increase H2O + Na output in urine, reduce plasma volume reducing cardiac preload + thus oedema
What are key diuretic examples which can be used for cardiac diseases? What does each one do?
- Loop e.g. Furosemide inhibits renal Na/K/2Cl transporter
- Thiazide e.g. hydrochlorothiazide inhibit renal Na/Cl symporter
- K-sparing e.g. spironolactone inhibit aldosterone activity
What are neprilysin inhibitors? Give an example.
New + promising treatment for heart failure with reduced EF
E.G. Sacubitril
What is the mechanism of action of neprilysin inhibitors?
- Neprilysin is major enzyme involved in breakdown of NPs
- Inhibition of neprilysin prolongs presence + activity of NPs
- NPs promote H2O + Na excretion
What drugs should neprilysin inhibitors be given with to be effective?
ARBs e.g. Valsartan
What can IV adrenaline be used for?
Treatment for cardiac arrest (acute heart failure)
What is the mechanism of action of adrenaline?
A is a powerful sympathomimetic + positive inotrope:
- Binds + stimulates cardiomyocyte B1-adrenergic receptors
2. Drives heart muscle contraction to restore heart function
What can IV atropine be used for?
Treatment for sinus bradycardia (acute heart failure)
What is the mechanism of action of atropine?
- Blocks M2 ACh receptors on cardiomyocytes
- Inhibits PS effects, cholinergic vagus nerve transmission which normally exert negative chronotropy
- Accelerates repolarisation rate in cardiac muscle
- Heart rate increased
Define sinus bradycardia.
Dangerously slow HR
Why can antiplatelet drugs be used to treat or prevent cardiovascular disease?
Platelet activation can drive thrombus formation leading to ACS
What are the major antiplatelet drugs?
Aspirin (COX inhibitor)
Clopidogrel (ADP receptor inhibitor)
What is the mechanism of action of ADP receptor inhibitors?
- Binds to + blocks function of ADP receptors on platelet surfaces
- Inhibits platelet activation + subsequent thrombus formation
What is the mechanism of action of COX inhibitors?
- Blocks enzyme action of platelet COX enzyme
- COX required for synthesis of TXA2 production
- Reduced TXA2 synthesis inhibits platelet activation + thrombus formation
What is the benefit of antiplatelet drugs and HMG-CoA reductase inhibitors used in the prevention or treatment of cardiovascular disease?
They do not affect BP
How do HMG-CoA reductase inhibitors (Statins) prevent cardiovascular disease?
Reduce circulating cholesterol levels + promote uptake of excess cholesterol from the bloodstream into the liver -> effective protection against atherosclerosis development
How is HMG-CoA reductase involved in cholesterol production?
Liver hepatocytes is main site of cholesterol production + it is secreted as LDL
HMG-CoA reductase is essential + rate-limiting step in cholesterol synthetic pathway
