Hyperlipidaemia, atherosclerosis and angina 2

Question 1

How do statins work?

Answer 1

block cholesterol synthesis in liver by competitively inhibiting HMG-Co A enzyme

Question 2

How is cholesterol removed from circulation?

Answer 2

increasing LDL receptors on surface and hepatocytes and removing LDL from circulation

Question 2

How is production of bile acid maintained?

Answer 2

liver compensates by removing cholesterol from circulation

Question 3

How to statins reduce cardiovascular risk?

Answer 3

reduction of LDL

Question 4

How do patients benefit?

Answer 4

produce small increases in the serum HDL concentration, reducing triglycerides (TG) and having anti-inflammatory effects that work against atherosclerotic plaque formation and rupture

Question 5

What do statins end with?

Answer 5

statin

eg: atorvastatin and simvastatin

Question 6

Who should take statins?

Answer 6

prescribed to reduce the risk that someone will have a heart attack, stroke or develop angina- primary or secondary prevention

Question 6

Adverse effects of statins (5)

Answer 6

• mild–> headache/GI tract issues
• myalgia (muscle pain)- 10%
• myositis–> muscle inflammation which had progress to rnhabdomylosis

rnhabdomylosis–> muscle breakdown- fatal as breakdown of muscle releases myoglobin to circulation- myoglobin is toxic to the kidney which can lead to acute kidney failure.

• may cause a small increase in the risk of developing type 2 diabetes (10-20% dependent on the particular statin).

Question 6

Primary prevention

Answer 6

trying to reduce the risk of cardiovascular disease occurring in the first place. The aim here is to reduce non-HDL cholesterol by 40%.

Question 7

Secondary prevention

Answer 7

reducing the risk of the person’s angina worsening if the disease is already established or reducing the risk of them suffering another heart attack or stroke

the doses of statins for secondary prevention higher than for primary prevention. NICE suggests a non-HDL cholesterol target of 2.6 mmol/L or lower.

Question 7

NICE guidelines on prevention

Answer 7

for secondary prevention, most people who have had a heart attack or stroke, or have been diagnosed with angina should be prescribed statins

a person who is at risk of developing cardiovascular disease is given statins
depending on QRISK calculator score

If someone’s 10 year risk of developing cardiovascular disease is 10% or higher= give statins

NICE suggested doctors should consider statins for some patients with a QRISK3 score of less than 10%- so number is increasing

Question 7

Statin and controversy

Answer 7

explosion in press interest in the statins has tended to exaggerate the risk of side effects, resulting in large numbers of people discontinuing their statin treatment

a 2016 review concluded that in the UK, up to 200000 patients had stopped their statin therapy and this could result in 2000-6000 avoidable heart attacks or strokes over the coming decade

Question 8

Statin substitutions

Answer 8

Although statins are the mainstays of drug treatment for hypercholesterolaemia, there are some patients who cannot tolerate them, or who do not achieve a big enough reduction in non-HDL cholesterol with statins alone

for these people, other drugs need to either be substituted for stains or added including ezetimibe and fibrates

Question 9

How does ezetimibe work?

Answer 9

blocks the absorption of dietary cholesterol by blocking NPC1L1

Question 9

Ezetimibe effectiveness

Answer 9

Ezetimibe is less effective on its own than the statins, producing smaller changes in LDL, HDL and triglycerides (TG), so given in combination with the statins

Dual approach - targeting both cholesterol synthesis and absorption of dietary cholesterol - can be effective for patients whose non-HDL cholesterol levels cannot be adequately controlled with statins alone e.g. people with familial hypercholesterolaemia

Question 10

When is ezetimibe used as sole therapy?

Answer 10

people who cannot tolerate statins as has similar but milder side effects compared to the statins

Question 11

Dual approach of ezetimibe

Answer 11

targeting both cholesterol synthesis and absorption of dietary cholesterol

Question 12

Fibrates examples

Answer 12

fenofibrate and gemfibrozil

Question 13

Fibrates

Answer 13

older class of drugs that used extensively before statins

activate nuclear hormone receptors known as the PPARs

modulate a range of genes involved in lipid metabolism

Question 14

Effects of fibrates (3)

Answer 14

1) raised HDL

2) lowered triglycerides (TG)

3) smaller effects on LDL cholesterol

Question 15

Effectiveness of fibrates

Answer 15

not as effective as statins at reducing non-HDL cholesterol so only used when statins cannot be tolerated or in patients with low HDL and high triglycerides

can be combined with statins, but this carries a high risk of rhabdomyolysis and so is only done under supervision by a specialist.

Question 16

Stable angina problem

Answer 16

some parts of the cardiac muscle do not receive sufficient oxygen because the blood vessels supply that muscle are blocked by atherosclerotic plaques

produces ischaemia which causes chest pain experienced in angina

Question 17

Outcomes of treatment strategies for stable angina (4)

Answer 17

preventing plaque worsening through the use of lipid-lowering drugs like the statins

using anti-thrombotic drugs to prevent the formation of a thrombus (blood clot) that would lead to a heart attack

using drugs to reduce the workload of the heart and decrease its oxygen needs.

improving blood flow to cardiac muscle using drugs or surgical techniques

Question 18

Glyceryl trinitrate

Answer 18

unstable high-explosive compound

when used as a medication it is either in a dilute solution or formulated with stabilizers so does not pose any risk of explosion

one of the main-stays of angina treatment and is usually prescribed in a short acting formulation that can relieve an attack of angina or prevent one occurring

Question 19

What should be done to a GTN before use?

Answer 19

GTN is a prodrug that must be converted to its active form nitric oxide (NO) before it can act.

Question 20

When is GTN ineffective?

Answer 20

if taken as a tablet that is swallowed because it is subject to extensive first-pass metabolism

Question 21

First-pass metabolism

Answer 21

when a drug is taken in conventional tablet form and swallowed it must be absorbed from the GI tract and enter the bloodstream many drugs are incompletely absorbed drugs that are absorbed must pass through the wall of the intestine and into the hepatic portal vein the cells lining the gastrointestinal tract have an array of enzymes whose purpose is to detoxify foreign substances and many drugs are metabolized before they enter the bloodstream the hepatic portal vein takes drugs to the liver which has wide range of enzymes that can break drugs down

Question 22

Bioavailability of GTN when taken orally

Answer 22

less than 1%.

Question 23

Alternative methods of drug delivery for GTN (4)

Answer 23

rectal ointment intravenous injections or infusions sublingual tablets or sprays transdermal patches

Question 23

What is bioavailability?

Answer 23

fraction of the drug that makes it into the systemic circulation

Question 24

Intravenous injections or infusions

Answer 24

used to treat more serious heart conditions such as unstable angina and congestive heart failure

Question 24

Rectal ointment

Answer 24

used for anal fissures not stable angina inconvinient

Question 25

Sublingual tablets or sprays

Answer 25

drug is either sprayed under the tongue or a tablet is placed there drug is then absorbed through mucous membranes in the mouth and passes into the circulation used to treat acute angina attacks but can also help prevent attacks most common way to take GTN provides immediate relief but has quite a short duration of action (20 to 30 minutes).

Question 26

Transdermal patches

Answer 26

The drug is slowly absorbed through the skin from a stick-on patch - similar to nicotine very convenient but are used mainly to prevent angina attacks and cannot be used to relieve acute angina. tolerance to the drug will develop and it will become less effective so some patients may need to limit their use of patches to around 12 hours per day.

Question 27

Isosorbide mononitrate

Answer 27

not subject to first pass metabolism so can be taken via the conventional oral route (swallowed) has a slower onset of action compared to GTN so it is not as suitable for relieving acute angina attacks

Question 28

How is isosorbide mononitrate given?

Answer 28

most commonly given in a sustained release formulation which means that the tablets are designed so they release the drug slowly over a long period of time

Question 29

What is isosorbide mononitrate used for?

Answer 29

prevent angina attacks but is normally only prescribed to patients who cannot tolerate one of the other preventer medications (calcium channel blockers, beta blockers) or as an add-on drug when the first-choice medications have not brought the angina under control

Question 30

Cellular actions

Answer 30

organic nitrates are broken down in the target tissues which are the endothelium and smooth muscle of blood vessels to yield the active principle which is gas nitric oxide

Question 30

What are all organic nitrates?

Answer 30

prodrugs

Question 31

What is nitric oxide?

Answer 31

an endogenous intracellular signalling molecule that activates soluble guanylyl cyclase this enzyme is the "G version" of adenylyl cyclase and turns GTP into cyclic GMP (cGMP)

Question 32

What does cGMP do?

Answer 32

cGMP activates protein kinase G sp protein kinase G can now phosphorylate target proteins in the cell this leads to a reduction in intracellular calcium which produces vasodilation

Question 33

Dilation of peripheral capacitance vessel

Answer 33

the force of contraction of cardiac muscle (and thus its oxygen demands) is proportional to the pre-load the more blood that returns to the heart, the harder it has to work if blood kept in the periphery, the heart will need less oxygen organic nitrates achieve this by dilating veins called capacitance vessels and this is their most important mechanism at lower doses - frank starling curve

Question 34

Dilation of peripheral arteries and arterioles

Answer 34

at higher doses organic nitrates dilate peripheral arteries and arterioles this reduces the after-load i.e. the resistance that the heart must push against when it contracts, thereby reducing its oxygen demand

Question 35

Dilation of coronary arteries

Answer 35

nitrates can also dilate larger coronary arteries but during an angina attack these may already be fully dilated particularly important in a form of angina called vasospastic angina where the ischaemia arises because a coronary artery has gone into a spasm of contraction nitrates can dilate these constricted arteries thereby relieving the ischaemic symptoms.

Question 35

Dilation of collateral vessels

Answer 35

in the heart small blood vessels called collateral vessels provide alternative pathways for the flow of blood act in the same way that a ring-road allows traffic to avoid a congested town centre these vessels can be dilated by organic nitrates, allowing blood to flow back into ischaemic areas

Question 36

Adverse effects of the organic nitrates

Answer 36

organic nitrates do not produce toxic metabolites and their adverse effects are primarily related to their powerful vasodilatory actions

Question 37

Side effects of organic nitrates (3)

Answer 37

1) headache 2) hypotension which can lead to dizziness and reflex tachycardia 3) dilate the blood vessels of the face- flushing

Question 38

When are surgical approaches used for angina?

Answer 38

if the drug options have not brought the angina under control

Question 39

2 types of surgical approaches used for angina

Answer 39

1) coronary artery angioplasty or PCI 2) coronary artery bypass graft (CABG)

Question 40

CABG difference to PCI

Answer 40

more invasive as it is open heart surgery ("heart bypass")

Question 41

What does CABG involve?

Answer 41

involves removing a non-essential blood vessel from another part of the body and using it to restore blood flow to part of the heart in which the blood supply is compromised

Question 42

When is CABG used?

Answer 42

CABG is used to treat angina that is resistant to drug treatment and where the location of the blockage means that PCI cannot be used

Question 42

What types of blood vessels are used for CABG?

Answer 42

internal mammary artery (from the chest) the great saphenous vein (from the leg)

Question 43

How to decide what is CABG procedure referred to as?

Answer 43

depending on the number of new connections that are made procedure may be referred to as a double bypass, triple bypass etc.

Question 44

How effective is CABG?

Answer 44

improves survival in patients who are high risk CABG more effective at controlling the symptoms of angina than drugs alone in terms of mortality and risk of heart attack it's superior to PCI in patients with severe coronary artery disease

Question 44

2 types of adverse effects of CABG

Answer 44

- those that arise from the surgery itself - poor wound healing, blood loss and dysrhythmias induced by the use of a general anesthetic - those from the graft

Question 45

Side effects of CABG (4)

Answer 45

myocardial infarction stroke cognitive decline but this has questioned recently (it has been suggested that the cognitive decline might be a consequence of the underlying cardiovascular disease rather than the procedure) grafts last up to 15 years, but will then need to be replaced this means repeated surgery if the patient is young.