Lecture 12 Ischaemic Heart Disease II Flashcards
What are the main aims of angina therapy
To keep the coronary plaques as stable as possible to avoid acute clot blockage and to reduce pain for the patient
What are the two types of approach in treating angina and how do they differ
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
Give some examples of symptomatic approaches to treating IHD
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
Which kinds of drugs are used as a prognostic approach in treating IHD
Aspirin statins β blockers and ACE inhibitors
Nitrates are the first line drugs used in angina how are they administered and how do they work
Nitrates are usually administered as a spray sublingually and work on the larger arteries to promote coronary vasodilation
What are the two mechanisms of nitrates
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
Outline the mechanism of action of nitric oxide
NO activates soluble guanylyl cyclase and increases cGMP which activates PKG. PKG then phosphorylates MLCP which dephosphorylates myosin leading to relaxation of smooth muscle.
Outline some of the adverse effects of nitrates
Marked hypotension headaches and tolerance
What causes tolerance in nitrate use
Nitrate tolerance is associated with a depletion of thiol groups (-SH) that are involved in the initial step of de-nitration of nitro-glycerine
Give an example of a short acting nitrate and how it is delivered
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
Give an example of a longer acting nitrate and how it is delivered
Isosorbide mononitrate is a longer acting nitrate that is orally administered 2x daily
What are Ca2+ channel blockers used in treating IHD
They non-selectively blocks the contraction of vascular smooth muscle by inhibiting L type Ca2+ channels
What are the three classes of Ca2+ channel blocker
Dihydropyridines (amlodipine) phenylalkylamines (verapamil) and benzothiazepines (diltiazem)
Which CCB is cardiac selective
Verapamil
What are the broad side effects of CCB use in IHD
Flushing and headache due to vasodilator action
What usual side effect is seen with verapamil
Verapamil can cause constipation due to effects on gastrointestinal nerves or smooth muscle
What are the main benefits of using aspirin to treat IHD
Aspirin reduces mortality and also the risk of a future heart attack
What class of drugs does aspirin belong to
NSAIDs
What is the mechanism of action of aspirin
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
How does aspirin mediate its anti-inflammatory effects
Through an inhibition of NFκ-B
Why does the action of aspirin last for a long period of time
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
How is aspirin absorbed and removed from the body
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
What are the side effects of aspirin use
GI bleeding deafness and tinnitus
Give an example of a drug which aspirin can interact with
Aspirin can lead to a massive increase in warfarin levels
Aspirin is an antiplatelet drug what other class of drugs is it often used in combination with in IHD
Anti-coagulant drugs such as heparin
Enoxaparin is another heparin like drug used as an anticoagulant. How does it act
Enoxaparin binds to and potentiates the anticoagulant antithrombin to form a complex that irreversibly inactivates clotting factor Xa.
What is the mechanism of action of K+ channel activators in the treatment of IHD
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
Give an example of a K+ channel activator used in IHD and explain how it acts
Nicorandil both acts as an NO donor causing relaxation of the smooth muscle but also activates K+ channels to cause dilation.
What are the main side effects of K+ channel activators
Headaches GI ulceration
What is the main contraindication of K+ channel activators
Phosphodiesterase inhibitors like sildenafil. This is contraindicated as using both can lead to marked hypotension
What analgesia is often used in ACS
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
Why is morphine often given with metoclopramide
Metoclopramide is an anti-emetic which prevents morphine from triggering the emesis response as a result of MOR agonism
Summarise the treatment for unstable angina
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
Summarise the treatment for NSTEMI
Analgesics to reduce the pain anti-platelet and anti-thrombotic therapy heparin possibly an additional platelet inhibitor. This is followed by PCI within 72hrs
How does treatment for STEMI differ from NSTEMI and unstable angina
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)
Give an example of a clot buster drug
Streptokinase
Outline the significance of inflammation in atherosclerosis
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
What cytokine is considered to be the master regulator of inflammation
IL-1
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
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
Where is IL-1 primarily derived from
Macrophages as well as the vessel wall
What are the two classes of IL-1
IL-1 Agonists – IL-1a and IL-1β. IL-1 Antagonists – IL-1ra
IL-1 is anti-inflammatory T or F
F – although IL-1ra is
What is meant when IL-1 is referred to as an acute phase reactant
It is released during a myocardial infarction
What is the effect of IL-1 agonists
Decreased contractility decrease apoptosis and increase leukocyte infiltration
What evidence is there for the role of IL-1 in inflammation in regard to atherosclerosis
IHC and ISH experiments have revealed increased IL-1β expression levels in the endothelium of atherosclerotic human coronary arteries
What animal model data suggests a role for IL-1 in atherosclerosis
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
What is canakinumab
A monoclonal antibody for IL-1β
How can CRP levels be used to measure the effect of a drug on inflammation in IHD
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
Discuss what these results show about the effect of canakinumab on CRP LDL and HDL levels
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
What does the data below tell us about the effect of canakinumab
Treatment with canakinumab was better than placebo in reducing the incidence of major adverse cardiac events in all of the groups
What were the conclusions from the CANTOS trial looking at the effect of canakinumab in the treatment of IHD
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
What is significant about canakinumab in terms of its target in the treatment of IHD
Canakinumab is the first drug for IHD that actually targets the cause the plaque itself
What are the downsides to using canakinumab to treat IHD
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
How do biological drugs differ from small molecules
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.
