Drugs for Ischaemic Heart Disease Flashcards
How many mitochondria are in each cardiomyocyte?
5000
Generate ATP- far more than any other organ of the body
What is preload?
Volume of blood in the ventricles at the end of diastole
What is preload determined by?
Blood volume
Venous tone, capacity of the venous circulation to hold blood (constriction= more return)
What is preload increased by?
Sympathetic NS activation
Renal failure
Heart failure
What is afterload?
Resistance the heart must overcome to circulate blood
What is afterload determined by?
Tone in arterial circulation
What is afterload increased by?
SNS activation
Hypertension
What causes narrowing of the coronary arteries?
Atheroma
Coronary artery spasm (smooth muscle spontaneously constrict)
leads to ischaemic heart disease
What do stable plaques lead to?
Lack of oxygen and chest pain (angina)
What leads to myocardial infarction?
Unstable plaque and thrombus
MINOCA= myocardial infarction non obstructed coronary artery
What does vascular endothelium regulate?
Blood vessel tone
Permeability
Leukocyte adhesion, platelet aggregation and tendency for thrombus formation
What occurs to lead to lesion formation?
Changes in endothelial function
Leukocyte adhesion and migration as endothelial permeability increases
What are the causes of endothelial dysfunction?
- Elevated and modified low density lipoprotein (in familial hypercholesterolaemia)
- Oxygen free radicals (smoking, hypertension, activated inflammatory cells)
- Infectious microorganisms (herpes virus, chlamydia pneumoniae, h. pylori)
- physical damage and gene activation by turbulent flow, high blood pressure
What are the risk factors for endothelial dysfunction?
Diabetes, ageing, male (females after menopause)
What are foam cells?
Macrophages that take up low density lipoprotein oxidised by interaction with oxygen free radicals
Describe the formation of a fatty streak
Inflammatory cell activation Smooth muscle migration Foam cell formation T cell activation Adherence and aggregation of platelets Adherence and entry of leukocytes
Describe the formation of advanced complex lesion
Macrophage accumulation
Formation of necrotic core
Fibrous cap formation- stability key to prognosis
Healing response to injury
What is the difference in outcome between unstable and stable angina?
Stable= chest pain Unstable= cap rupture or erosion= thrombus= heart attack/MI, stroke
Which drug lowers cholesterol and low density lipoprotein?
Statins
simvastatin
How is LDL formed?
HMG CoA into mevalonate via HMG CoA reductase (rate determining step in liver)
Mevalonate precursor for cholesterol, then LDL
binds to LDL receptors for clearance
What is the mechanism of statin drug action?
statins are inhibitors of HMG CoA reductase
Increase expression of LDL receptors (so more clearance)
What are the other effects of statins (pleiotropic)?
Improved endothelial function Inhibition of inflammation Plaque stabilisation Inhibition of thrombus formation (mevalonate compounds involved in intracellular signal transduction)
What other lipid lowering drugs are used with or as an alternative to statins?
Fibrates (bezafibrate, gemfibrozil, fenofibrate)
ezetimibe
Describe fibrates
Activate intracellular PPARa (peroxisome proliferator receptor a)
Decrease circulating very low density lipoprotein and triglyceride, only very small effect on LDL but also increase protective high density lipoprotein
Describe ezetimibe
Lowers cholesterol absorption from small intestine vis action in epithelial cells
What is angina pectoris?
Intermittent chest pain caused by mismatch between demand of oxygen by the heart and supply of oxygen to the heart (stimulates chemoreceptors- chest pain)
What is oxygen supply decreased by?
Coronary artery disease
Anaemia
What is oxygen demand increased by?
Exercise
Tachycardia
Hypertension
What is the aim of angina treatment?
Reduce demand or increase supply
Reduce demand by reduce heart rate/ force of contraction/ preload/ afterload
Describe acute angina treatment
Rest
Rapid acting organic nitrate (glyceryl trinitrate)
Describe prophylactic angina treatment
Targets blood vessels- longer lasting nitrate/ K (ATP) channel opener
Targets heart- beta adrenoreceptor antagonist/ calcium antagonist/ funny channel blocker
How do nitrates affect the blood vessels?
NO in endothelial cells into smooth muscle cell- guanylate cyclase converts GTP into cGMP= relaxation (reduces availability for Ca 2 for contraction)
Veins more than arteries
What are the effects of nitrates on venous circulation?
Dilate veins, decrease venous return and preload on heart, reduce oxygen demand
What are the effects of nitrates on arterioles and coronary arteries?
Dilate and reduce afterload on heart therefore reduce oxygen demand
Coronary= improves supply (coronary spasm)
What are examples of nitrates?
- Glyceryl trinitrate- acute (sub-lingual or spray), chronic use leads to tolerance (loss of responsiveness) rapid action
- Isosorbide dinitrate- slow release patch/ oral, can be prophylactic, nitrate free periods required, longer acting
What are the effects of nicorandil?
Reduces preload and afterload on heart and therefore oxygen demand
Dilates coronary arteries and can increase oxygen supply in coronary spasm
What are the mechanisms of nicorandil?
Causes blood vessel dilation by opening ATP sensitive K+ channels in smooth muscle cells Nitrate moiety (releases NO) in structure therefore additional vasodilator action
What are the mechanisms and effects of beta adrenoreceptor antagonists (like atenolol)?
- Blocks cardiac beta 1 adrenoreceptor= reduce heart rate and therefore oxygen demand
- Blocks renal beta 1 adrenoreceptor= reduce blood volume by reducing renin release and activation of RAAS, reduce preload and therefore oxygen demand
What does RAAS stand for?
Renin Angiotensin Aldosterone System
What are the mechanisms and effect of ivabradine?
Blocks ‘funny current’ in sino-atrial node cells= reduces rate of spontaneous depolarisation during action potential generation- reduce heart rate so oxygen demand
(Less side effects than beta blockers)
What are the mechanisms and effects of calcium antagonists?
nifedipine, diltiazem
Prevent opening of voltage dependent Ca 2 channels= prevents Ca 2 entry into cardiac muscle cells from extracellular space= reduce availability to contractile apparatus= reduce force of contraction and therefore oxygen demand
Describe thrombus formation
Endothelial cells produce anti-thrombotic mediators, damage= collagen exposure= platelet activation (change shape and stick together)= coagulation cascade= fibrin
What are anti-thrombotic drugs?
Taken prophylactically to reduce risk of thrombus if atherosclerotic plaque ruptures, in patients at high risk or already had MI
- Anti-platelet (aspirin, clopidogrel, vorapaxar)
- Anti-coagulant (warfarin, rivaroxaban)
Describe platelet activation
Stimulus (collagen)- thrombin activates coagulation cascade- Arachidonic acid via phospholipaseA2- cyclic endoperoxidases via cyclooxygenase (COX)- TxA2 prostaglandin via Tx synthetase- TxA2 receptor= increase in iCa 2+ so activation of platelet
What is the mechanism of anti-platelet drugs?
Thrombin antagonist
COX inhibitor
How do platelets further increase activation?
Activated platelets change shape and release contents of granules- adenosine diphosphate (ADP)
How do activated platelets stabilise the thrombus?
Platelets express glycoprotein 2b/3a receptors for attachment of fibrin, from coagulation cascade
What other mechanisms of anti-platelet drugs have directly on the platelet?
P2Y12 receptor antagonists to block ADP so less platelet aggregation abciximab antibody (IV)- blocks fibrin binding to gp2b/3a
What are the overall mechanisms of anti-platelet drugs?
- COX inhibitor- aspirin- irreversible inhibition of COX, prevents formation of TxA2 and platelet activation
- P2Y12 inhibitor- clopidogrel, ticagrelor- blocks effect of ADP and prevents platelet activation
- Thrombin-receptor antagonist- vorapaxar- prevent activation of PAR-1 receptors on platelets
What are the risks of anti-platelet drugs?
Bleeding
Newer drugs shorter acting or reversible
What are anti-coagulant drugs and what are the types?
Prevent the formation of fibrin to stabilise platelet plug
- Intravenous= heparin
- Orally active= warfarin, rivaroxaban
What is the action of heparin?
Binds to Anti-thrombin 3- released by endothelial cells naturally in response
Promotes action, reduces coagulation cascade
What is the action of warfarin?
Reduces the action of enzyme reductase so less oxidised Vitamin K is converted into hydroquinone Vitamin K so less Glu converted into Glu-COOH which is involved in active factors 2,7,9,10 (prevents cofactors forming)
What are the common indications of warfarin?
AF, artificial heart valves, DVT, pulmonary embolism, occasionally after MI
What are the cons of warfarin?
Narrow optimal range, high risk of bleeding
Broken down in liver, enzymes induced by other drugs, environmental influences
Blood levels must be checked regularly
What is the action of rivaroxaban?
Inhibits action of Xa in thrombin formation
