Lecture 12 Ischaemic Heart Disease II

Question 1

What are the main aims of angina therapy

Answer 1

To keep the coronary plaques as stable as possible to avoid acute clot blockage and to reduce pain for the patient

Question 2

What are the two types of approach in treating angina and how do they differ

Answer 2

Symptomatic – Reduce the symptoms by reducing strain on the heart by increasing the vasodilation of the arteries and veins. Prognostic – to improve the outcome for the patient

Question 3

Give some examples of symptomatic approaches to treating IHD

Answer 3

Nitrates (such as glyceryl trinitrate and isosorbide mononitrate to increase vasodilation. Aspirin and antiplatelet drugs to decrease the chance of thrombotic event. Ca2+ channel blockers and/or K+ channel activators. Morphine to reduce the pain

Question 4

Which kinds of drugs are used as a prognostic approach in treating IHD

Answer 4

Aspirin statins β blockers and ACE inhibitors

Question 5

Nitrates are the first line drugs used in angina how are they administered and how do they work

Answer 5

Nitrates are usually administered as a spray sublingually and work on the larger arteries to promote coronary vasodilation

Question 6

What are the two mechanisms of nitrates

Answer 6

The primary mechanism is to relax vascular smooth muscle but the secondary mechanism acts to reduce cardiac work by a redirection of flow towards the ischaemic areas of heart muscle

Question 7

Outline the mechanism of action of nitric oxide

Answer 7

NO activates soluble guanylyl cyclase and increases cGMP which activates PKG. PKG then phosphorylates MLCP which dephosphorylates myosin leading to relaxation of smooth muscle.

Question 8

Outline some of the adverse effects of nitrates

Answer 8

Marked hypotension headaches and tolerance

Question 9

What causes tolerance in nitrate use

Answer 9

Nitrate tolerance is associated with a depletion of thiol groups (-SH) that are involved in the initial step of de-nitration of nitro-glycerine

Question 10

Give an example of a short acting nitrate and how it is delivered

Answer 10

Glycerine trinitrate (GTN) is a short acting nitrate that is administered sublingually and is effective within 1-2 minutes. Its duration of effects last around 30mins

Question 11

Give an example of a longer acting nitrate and how it is delivered

Answer 11

Isosorbide mononitrate is a longer acting nitrate that is orally administered 2x daily

Question 12

What are Ca2+ channel blockers used in treating IHD

Answer 12

They non-selectively blocks the contraction of vascular smooth muscle by inhibiting L type Ca2+ channels

Question 13

What are the three classes of Ca2+ channel blocker

Answer 13

Dihydropyridines (amlodipine) phenylalkylamines (verapamil) and benzothiazepines (diltiazem)

Question 14

Which CCB is cardiac selective

Answer 14

Verapamil

Question 15

What are the broad side effects of CCB use in IHD

Answer 15

Flushing and headache due to vasodilator action

Question 16

What usual side effect is seen with verapamil

Answer 16

Verapamil can cause constipation due to effects on gastrointestinal nerves or smooth muscle

Question 17

What are the main benefits of using aspirin to treat IHD

Answer 17

Aspirin reduces mortality and also the risk of a future heart attack

Question 18

What class of drugs does aspirin belong to

Answer 18

NSAIDs

Question 19

What is the mechanism of action of aspirin

Answer 19

Aspirin irreversibly acetylates COX enzymes preventing the conversion of arachidonic acid to prostaglandin H2. This in turn prevents the production of thromboxane A2 which stimulates platelet aggregation

Question 20

How does aspirin mediate its anti-inflammatory effects

Answer 20

Through an inhibition of NFκ-B

Question 21

Why does the action of aspirin last for a long period of time

Answer 21

Aspirin is known as a suicide inhibitor. Because it forms a covalent bond with COX aspirin binds permanently to the enzyme. Hence the duration of aspirin’s effects depends on ability of the body to synthesise new COX enzymes. Aspirins effects of platelets last even longer as they are enucleate and so can’t make any more COX enzyme hence its acts for the lifetime of the platelet which is around 10 days

Question 22

How is aspirin absorbed and removed from the body

Answer 22

Aspirin is a weak acid and so is protonated in the stomach making it able to cross the mucosa. The majority however is absorbed in the ileum due to the high surface area created by the villi. The majority of the aspirin is hydrolysed in 30mins by esterase’s in the liver (75% metabolised in the liver) but also plasma

Question 23

What are the side effects of aspirin use

Answer 23

GI bleeding deafness and tinnitus

Question 24

Give an example of a drug which aspirin can interact with

Answer 24

Aspirin can lead to a massive increase in warfarin levels

Question 25

Aspirin is an antiplatelet drug what other class of drugs is it often used in combination with in IHD

Answer 25

Anti-coagulant drugs such as heparin

Question 26

Enoxaparin is another heparin like drug used as an anticoagulant. How does it act

Answer 26

Enoxaparin binds to and potentiates the anticoagulant antithrombin to form a complex that irreversibly inactivates clotting factor Xa.

Question 27

What is the mechanism of action of K+ channel activators in the treatment of IHD

Answer 27

K+ channel activation leads to K+ efflux and a hyperpolarisation of the membrane potential which in turn acts to decrease Ca2+ levels. This leads to decreased vasoconstriction

Question 28

Give an example of a K+ channel activator used in IHD and explain how it acts

Answer 28

Nicorandil both acts as an NO donor causing relaxation of the smooth muscle but also activates K+ channels to cause dilation.

Question 29

What are the main side effects of K+ channel activators

Answer 29

Headaches GI ulceration

Question 30

What is the main contraindication of K+ channel activators

Answer 30

Phosphodiesterase inhibitors like sildenafil. This is contraindicated as using both can lead to marked hypotension

Question 31

What analgesia is often used in ACS

Answer 31

Morphine is often given in the ambulance. This is usually well-tolerated and binds to μ opioid receptors (Gi/Go coupled to ion channels) in the brain as a partial agonist

Question 32

Why is morphine often given with metoclopramide

Answer 32

Metoclopramide is an anti-emetic which prevents morphine from triggering the emesis response as a result of MOR agonism

Question 33

Summarise the treatment for unstable angina

Answer 33

Analgesics to reduce the pain DAPT combining aspirin with clopidogrel/prasugrel/ticagrelor heparin secondary prevention in the form of statins ACE inhibitors or β blockers. This is followed by PCI once the patient is stabilised

Question 34

Summarise the treatment for NSTEMI

Answer 34

Analgesics to reduce the pain anti-platelet and anti-thrombotic therapy heparin possibly an additional platelet inhibitor. This is followed by PCI within 72hrs

Question 35

How does treatment for STEMI differ from NSTEMI and unstable angina

Answer 35

The patient is taken to the closest tertiary heart attack centre where primary PCI is given upon admission. If transfer time to heart attack centre is long then a clot buster is given (over 120mins). Following PCI the patient is then put onto DAPT (aspirin + ticagrelor)

Question 36

Give an example of a clot buster drug

Answer 36

Streptokinase

Question 37

Outline the significance of inflammation in atherosclerosis

Answer 37

Inflammation is a process occurring throughout development of atherosclerosis. It is thought that inflammation in the artery wall is the initial trigger for plaque rupture whereby the flow of blood contacts the inside of the vessel wall due to breakdown of the glycocalyx driven by inflammation

Question 38

What cytokine is considered to be the master regulator of inflammation

Answer 38

IL-1

Question 39

We know that inflammation is a key process in atherosclerosis and that there are master regulators of the process as well as that excess inflammation in plaques is bad. What then are the downsides to targeting inflammation in atherosclerosis and IHD

Answer 39

Firstly inflammatory protein responses are individualised which could make targeting it difficult. In addition blocking key regulators of inflammation may leave individuals susceptible to infection with aggressive reductions in inflammation leading to thinner caps on plaques making some more prone to rupture

Question 40

Where is IL-1 primarily derived from

Answer 40

Macrophages as well as the vessel wall

Question 41

What are the two classes of IL-1

Answer 41

IL-1 Agonists – IL-1a and IL-1β. IL-1 Antagonists – IL-1ra

Question 42

IL-1 is anti-inflammatory T or F

Answer 42

F – although IL-1ra is

Question 43

What is meant when IL-1 is referred to as an acute phase reactant

Answer 43

It is released during a myocardial infarction

Question 44

What is the effect of IL-1 agonists

Answer 44

Decreased contractility decrease apoptosis and increase leukocyte infiltration

Question 45

What evidence is there for the role of IL-1 in inflammation in regard to atherosclerosis

Answer 45

IHC and ISH experiments have revealed increased IL-1β expression levels in the endothelium of atherosclerotic human coronary arteries

Question 46

What animal model data suggests a role for IL-1 in atherosclerosis

Answer 46

IL-R1 knockout mice have a less severe atherosclerotic phenotype suggesting that IL-1 agonists seemingly contribute to the development of the disease. Similarly treatment atherosclerotic mice with the IL-1 antagonist IL-1ra decreased the inflammation seen in the vessels

Question 47

What is canakinumab

Answer 47

A monoclonal antibody for IL-1β

Question 48

How can CRP levels be used to measure the effect of a drug on inflammation in IHD

Answer 48

C reactive protein (CRP) is an acute phase reactant protein made by the liver. It is released into the bloodstream within hours of MI injury infection or inflammation. Hence it can be used to give an indication of the degree of inflammation

Question 49

Discuss what these results show about the effect of canakinumab on CRP LDL and HDL levels

Answer 49

This data shows a dose-dependent decrease in CRP levels with increasing concentrations of canakinumab suggesting its ability to inhibit inflammation. In addition the drug had no effects of lipids suggesting that this treatment is specific for IL-1 and inflammation

Question 50

What does the data below tell us about the effect of canakinumab

Answer 50

Treatment with canakinumab was better than placebo in reducing the incidence of major adverse cardiac events in all of the groups

Question 51

What were the conclusions from the CANTOS trial looking at the effect of canakinumab in the treatment of IHD

Answer 51

Inhibition of IL-1β with subcutaneous canakinumab substantially lowered inflammatory biomarkers hsCRP and IL-6. Its effects were specific for inflammation as there was no beneficial impact on atherogenic lipids. Finally canakinumab significantly reduced subsequent heart attacks

Question 52

What is significant about canakinumab in terms of its target in the treatment of IHD

Answer 52

Canakinumab is the first drug for IHD that actually targets the cause the plaque itself

Question 53

What are the downsides to using canakinumab to treat IHD

Answer 53

As it is a monoclonal antibody it is extremely expensive at £10000 per person per annum. In addition the CANTOS trial revealed there was an increased risk of fatal infection as well as the incidence of lung cancer increasing whilst on the drug

Question 54

How do biological drugs differ from small molecules

Answer 54

Biologicals are usually protein based heat sensitive drugs that are large (>150KDa) molecules. They are often administered parenterally and are highly selective and specific with a long half-life. The downsides are that they are slowly absorbed with a small volume of distribution and their movement into tissues is different only occurring by the transcellular pathway.