Pharmacology - CV Drugs 2 - Flashcards in University Pharmacy

How are the symptoms of angina described?

Seized whilst walking, painful, gets worse over time. Angina - symptom of CHD. ~5% incidence in population. Overall prognosis in angina patients in good but symptom control can be difficult

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Describe features of atherosclerosis (1)

Build up of cholesterol rich plaques (cause of angina) causes stenosis of coronary arteries (narrowing). Fibrous cap (smooth muscle cells/connective tissue)

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Describe features of atherosclerosis (2)

Atheroma (soft pool of extracellular lipid/cell debris, activated immune cells, calcifies over time). Plaques generally form in proximal region of coronaries within 6 cm of aorta. Angina (no rupture). Acute coronary syndrome (rupture)

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Describe features of atherosclerosis (3)

Can result in aneurysm, affect renal blood vessels (chronic kidney disease) and carotid arteries (stroke - when there is a rupture)

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What are the two extremes of the type of plaque? - stable angina (1)

Thick fibrous cap, small atheroma, lumen narrowed, leads to stable angina, loss of coronary flow reserve (ability to increase flow of blood), cannot vasodilate. Pain due to insufficient blood supply, precipitated by increase in myocardial O2 demand

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What are the two extremes of the type of plaque? - stable angina (2)

Fibrous cap doesn't rupture due to being so thick

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What are the two extremes of the type of plaque? - unstable angina/NSTEMI/STEMI

Thin fibrous cap, can rupture, thrombosis occurs, develop acute coronary syndrome

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Describe features of angina of effort (1)

Symptoms (tightness, squeezing, crushing sensation in the chest) vary in people. Due to exertion/emotion, stops at rest (heart doesn't need increased blood flow) or GTN

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Describe features of angina of effort (2)

Results in increase from oxygen demand with restricted blood flow due to fixed stenosis. Decreased in O2 in cardiac tissue - release of protons/bradykinin - activated TRPV1 on sensory nerves - pain - release of SP - coronary vasodilation

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Describe features of angina of effort (3)

Process could help improve condition but not enough due to narrowing of lumen. Angina of effort develops with stenosis of >70% of vessel lumen

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Describe features for microvascular angina (syndrome X) (1)

No stenosis, people can become ischaemic/develop angina of effort. Exercise (coronary dilation). But microvascular doesn't dilate (resistance to blood flow doesn't decrease/lack of blood supply to the heart/coronary reserve is insufficient)

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Describe features for microvascular angina (syndrome X) (2)

Due to dysfunctional endothelium. Chest pain, normal coronary angiogram, positive exercise test - condition occurs more commonly in women

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Describe features of mixed angina (variable threshold)

Not associated with stenosis but the vasospasm of coronary arteries. Can affect people at night. Combination of Prinzmetals and angina of effort. Unpredictable, develops at different levels of exercise (stenosis/vasospasm) - very common

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Describe features of vasospastic (Prizmetal's) angina

Decreased O2 supply due to spasm of coronary artery, occurs at rest, often at night

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Describe features of unstable angina

Decreased O2 supply, due to transient formation of non-occlusive thrombus - an acute coronary syndrome

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What are the aims of the drug treatment? (1)

Limit the number, severity and sequellae of anginal attacks (improve quality of life). Main mechanisms involve treatment of angina of effort by decreasing cardiac O2 demand

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What are the aims of the drug treatment? (2)

Or increase O2 supply to ischaemic zone by decreasing HR and increase blood flow in coronary arteries

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What are the aims of the drug treatment? (3)

Protect against future, potentially more lethal ischaemic syndromes (e.g. MI) and lower risk of atherosclerosis progression (decrease risk factors e.g. smoking/BP/cholesterol, aspirin, beta blockers, ACE-I, statins)

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What is the main action of nitrates?

Dilate veins, decrease preload, heart stretches less (works less hard, less pumping), reduce central venous pressure, decrease wall tension, reduce O2 demand

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What is the main action of beta blockers?

Makes heart work less hard, reduces CO

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What is the main action of the calcium channel blockers?

Vasodilators, reduce arteriole constriction, reduce afterload (amount of work the heart has to do to propel blood into the aortic, determined by BP in aorta), heart works less hard, reduce O2 demand

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What is the main action of K-ATP channel activators?

Reduce afterload, dilate coronary arteries

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What is the main action of ivabradine?

Slows down the heart, use less energy, perfusion of heart (LV)/allows heart to get more blood during diastole

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What is the main action of ranolazine?

Reduces cardiac stiffness, energy is conserved, reduces cardiac work

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Outline the NICE treatment pathway for angina (1)

Use short acting nitrate for immediate relief/short term prevention

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Outline the NICE treatment pathway for angina (2)

For ongoing prophylaxis - (1) beta blocker or CCB, (2) beta blocker + vascular selective CCB, (3) beta blocker + vascular selective CCB + long acting nitrate/ivabradine/nicorandil/ranolazine

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Outline the NICE treatment pathway for angina (3)

Clinical trial evidence demonstrating the superiority of any of these drugs is lacking (based on expert consensus). New approach - individually tailor treatment based on type of angina and co-morbidities

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Describe features of organic nitrates (1)

NO donor. Reduces venous pressure/increase coronary blood flow, preferential venodilators. Glyceral trinitrate (sublingual), rapid effect, stops short angina attack/prevents attack. NO2 groups reduced to NO (also released by endothelium)

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Describe features of organic nitrates (2)

Longer acting organic nitrates (isosorbide dinitrate) taken on an ongoing basis (pills/ointments/patches). Effectiveness limited by development of tolerance after 12 hrs

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Describe features of organic nitrates (3)

Overcome tolerance by having a daily 8 hr free period (usually at night)

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Describe pharmacology of organic nitrates (1)

High potency nitrates (GTN) metabolised by mtADH - gives rise to NO2 - reduced to NO. GDN is further metabolised by CYP450 - gives rise to more NO. Low potency nitrates are metabolised by CYP450 to give NO

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Describe pharmacology of organic nitrates (2)

Issue - metabolism of NO can give rise to reactive oxygen species. Build up of superoxide in cells - binds to NO to form peroxide - NO not effective (tolerance occurs/build up of reactive oxygen species)

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What are the major actions of organic nitrates?

Venodilation (reduced preload) at low doses. Higher doses - arteries dilate (reduce afterload) and arterioles dilate (reduce BP). Reduce central venous pressure/afterload, fall in cardiac wall tension, reduce cardiac O2 demand

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What are the minor actions of organic nitrates?

Dilate larger coronary arteries, increase blood flow through coronary collaterals, reduce TPR/afterload, decrease cardiac O2 demand

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What are the side effects and issues with organic nitrates?

Side effects - headache, facial flushing, reduce BP (detected by baroreceptors), reflex increase HR. Issues - tolerance, high first pass metabolism (not taken as tablet swallowed but as a tablet dissolving in the mouth or a patch)

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Describe features of collaterals (1)

Plaque leads to formation of ischaemia. Leads to growth of collaterals (branches between coronary arteries), region of heart able to reach blood supply (by-pass stenosis), not sufficient to prevent ischaemia

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Describe features of collaterals (2)

Dilation of coronary arteries leads to more blood flow through collaterals (potential mechanism for nitrates)

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Describe features of beta blockers (1)

E.g. bisoprolol (b1-selective). Inhibit sympathetic stimulation of the heart (caused in adrenaline/NA). Aim for a resting HR of 55-60 bpm and an increase of <75% of the rate causing ischaemia during exercise. Slow HR/beat less strongly

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Describe features of beta blockers (2)

Reduce O2 demand, increase coronary flow (to increase O2 supply). Reduce after load and BP. Longer diastole. Beta blockers increase life expectancy post-MI. Dose patient based on results from exercise test (effort required until angina occurs)

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Describe features of calcium channel blockers (1)

E.g. amlodipine (DHP), verapamil, diltiazem. Vasodilation - DHPs > diltiazem > verapamil. Negative inotropy - verapamil > diltiazem > DHPs

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Describe features of calcium channel blockers (2)

DHPs act by vasodilation - reduce afterload/cardiac work. Verapamil acts by direct negative inotropic effect (some reduction in afterload). CCBs increase coronary flow (useful in angina linked with coronary vasoconstriction e.g. Prinzmetal's/mixed)

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Describe features of calcium channel blockers (3)

Other potential beneficial actions - reduce reperfusion injury, endothelial protection, reduce atheroma progression, reduce LV hypertrophy

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Describe features of K-ATP channel activators - nicorandil (1)

Dual action (opens ATP-sensitive K+ channels in vascular smooth muscle cells, stimulates guanylate cyclase/increase vascular smooth muscle cell [cGMP]). Closes Ca channels/less Ca influx

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Describe features of K-ATP channel activators - nicorandil (2)

Relaxation of vascular smooth muscle through multiple mechanisms - hyperpolarisation, removal of Ca from cytoplasm, Ca densitisation. Venous/arterole dilation (decrease preload/afterload/cardic O2 demand)

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What are the side effects and contraindications of nicorandil?

Headache, flushing, GI upset, rarely cause ulceration of GIT, skin. Contra-indicated in patients with low BP, those using PDE5 inhibitors (phosphodiesterase breaks down cGMP, leads to more cGMP/reduce BP/shock), pregnancy/breast-feeding

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Describe features of ivabradine (1)

Slows down the heart, allows more time during diastole for heart to be perfused with blood. Blocks channel in SAN (pacemaker). Enters open channel from the inside, gets trapped when channel shuts

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Describe features of ivabradine (2)

Open channel block - binding of ivabradine in channel builds up when channel is opening more frequently. Use-dependency - ivabradine tends to block more when HR goes up (beneficial/wants to reduce HR)

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Describe features of ivabradine (3)

Lower HR allows more time for blood to perfuse the myocardium, reducing ischaemia. Lower HR reduces afterload (aorta filled with less blood) and decrease O2 demand

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Describe features of ranolazine (1)

Thought to help with angina but inhibiting fatty acid oxidation. Promotes glucose oxidation/glycolysis which increases myocyte energy production. Now thought to act by inhibiting the late Na+ current in myocytes

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Describe features of ranolazine (2)

Myocardium is ischaemic/hyperoxic/reperfusion - increase ROS - increase late Na+ current - more sodium into cell - raises intracellular Ca conc (reverse mode NCX) - cells don't relax properly between heart beats -

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Describe features of ranolazine (3)

Heart becomes stiffer (increases energy for pump) - reduce CO (less blood filling in the heart) - increase cardiac work (happens during angina/due to being ischaemic)

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Describe features of ranolazine (4)

But increase in Na influx can also lead to AP prolongation - after depolarisations - arrhythmias. Current only lasts for milliseconds (doesn't shut off for reverse mode NCX, longer lasting)

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Describe features of revascularisation (1)

Stenosis. Percutaneous transluminal coronary angioplasty (PTCA). PCI. Balloon inflated to open up stenosis. Have adequate blood flow. Issue - restenosis can occur in 30% of patients over 6 months, symptoms return (solution - stents)

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Describe features of revascularisation (2)

COURAGE trial. Compared revascularisation with pharmacological treatment (metoprolol, amlodipine, nitrates, beta blockers etc.). Results showed over time that surgery and pharmacological treatment had similar beneficial outcomes for the patients

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Outline the treatment for acute coronary syndromes

Chest pain/other symptoms/suspected MI - electrocardiogram - (1) ST segment elevation - STEMI (GRACE score for diagnosis). (2) - no ST segment elevation - increase in troponin (NSTEMI) or no increase in troponin (unstable angina). NSTE-ACS

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What is the treatment for unstable angina/NSTEMI?

Immediately given aspirin. On diagnosis - low mwt heparin (in hospital). Ticagrelo (for 1 year). Glycoprotein IIb/IIIa antagonists (used but uncommon). Beta blockers and ACE- indefinitely (reduce risk of developing chronic heart failure)

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What is the treatment for STEMI? (1)

Immediately (in ambulance) given aspirin, ADP antagonist (suppress further thrombosis), morphine (vasodilator/reduce pain/anxiety), beta blocker (decrease infarct size, reduce mortality). PCI within 90 mins or thrombolytics within 30 mins

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What is the treatment for STEMI? (2)

Treatment to remove clot must be carried out within 12 hours in order to have a beneficial effect. Follow up treatment - aspirin (life-long), ticagrelor (1 year) to reduce risk of another thrombosis

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What is the treatment for STEMI? (3)

Beta blocker, ACE-I indefinitely reduce risk of developing chronic heart failure

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Outline the process for thrombus formation and dissolution (1)

Secretion of ADP, synthesis of mediators (PAF, TXA), adhesion/activation/aggregation of platelets, activation of clotting cascade, thrombin polymerises, thrombus forms, plasmin dissolves in clot

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Outline the process for thrombus formation and dissolution (2)

Aspirin/ticagrelor prevents further platelet aggregation. LMW heparins block the clotting cascade (stop polymerisation of thrombin)

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Describe features of aspirin (1)

Used to decrease risk of arterial thrombosis by reducing platelet aggregation. Aggregation is promoted by thomboxane A2 and inhibited by prostacyclin. Aspirin blocks the synthesis of TXA2 and PGI2. Platelets/fragment cells. Endothelial (make protein)

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Describe features of aspirin (2)

Aspirin irreversibly inhibits COX to block synthesis of TXA2/PGI2. Endothelial cells synthesise new COX protein, platelets cannot. PGI2 release recovers more quickly than TXA2 (anti-aggregatory effect of PGI2 predominates)

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Describe features of aspirin (3)

Anti-inflammatory/anti-pyretic effects of aspirin are mainly due to inhibition of PGE2 synthesis

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Describe features of aspirin (4)

Low dose (75 mg) used prophylactically to reduce risk of thrombus formation. Rapid absorption, metabolised to salicylate in liver/GIT (more important for anti-inflammatory effect compared to anti-thrombotic action)

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Describe features of aspirin (5)

Begins to inhibit platelet aggregation within 60 mins. Plasma t 1/2 only 20 mins but anti-thrombotic effect lasts several days. Depends on platelet turnover, two days may be sufficient for normal haemostasis to be re-established (so given daily)

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Describe features of ticagrelor (1)

Reversibly/non-competitively blocks ADP receptors (P2Y12) on platelets. Inhibits activation of GPIIb/IIIa receptors, preventing fibrin binding and clot formation

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Describe features of ticagrelor (2)

Used for long term prophylaxis against thrombosis in patients who have suffered an acute coronary syndrome. Generally combined with aspirin or used alone in aspirin-intolerant patients

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What are the main adverse effects of ticagrelor?

SOB, bleeding (GIT, nose bleed), 5% of people suffer ventricular pauses of several seconds during initial week of treatment. CI in patients with existing or history of pathological bleeding and arrhythmias

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What does ticagrelor interact with?

Statins (increases statin concentration) and grapefruit juice (blocks CYP3A4 which metabolises ticagrelor)

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Pharmacology - CV Drugs 2

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