Cardiovascular Disease & Risk Factors (5) Ischaemic heart disease

Question 1

Ischaemic Heart Disease

Answer 1

Atherosclerosis in coronary arteries, narrower and stiffer
>not a problem until you exercise or experience stress
>Physical manifestation of the atherosclerosis
>sharp chest pain -> angina

Question 2

O2 supply of the heart

Answer 2

Coronary arteries supply blood to cardiac muscle
>O2 supply depends on coronary artery flow

To increase flow
>Dilate coronary arteries
(hard to do this with angina, arteries are occluded and stiff, might not be the best choice of treatment in angina)

> Decrease heart rate - arteries less compressed
>very little perfusion of the heart muscle occurs during systole (endocardial vessels compressed because muscle is compressed)
>during diastole, muscle relaxed, vessels relaxed, this is when most perfusion of cardiac muscle happens (increase o2 supply to that muscle by reducing HR this way)

Question 3

O2 demand of the heart

Answer 3

O2 demand depends on cardiac workload (how to reduce O2 demand and make the heart work less)

> Cardiac output = HR x SV
Preload = degree of stretch pre-contraction
(BV more diluted, lower preload because more blood will be stored in the venous reservoir)
Afterload = resistance heart pumps against
(reduce pressure by which the left ventricle has to push out against, reduce TPR, reduces afterload)

Question 4

Angina Pectoris - Definition

Answer 4

Ischaemic heart disease causes angina

> imbalance between o2 supply/o2 needs
insufficient o2 to meet cardiac demand
reduced perfusion rather than inadequate blood o2

Angina caused by hypoxia
>get production of pain producing substances, bind to pain receptors in heart, produce excruciating pain in angina

Question 5

Angina - Therapy varies with type

Answer 5

Stable angina (classic, effort)
>will focus on stable angina = occurs when perfusion of cardiac muscle is sufficient at rest but can experience acute angina attack when get exertion/stressed
>adrenaline released, increase in contractility, HR increase, B1 receptors, get angina attack
>associated with coronary artery disease

Variant angina (vasospastic)
>coronary vasospasm at rest
>Mediator unknown

Unstable angina (crescendo, rest)
>angina at rest and with effort
>pain gets worse and worse, progresses to myocardial infarc
>potential for thrombi formation

Question 6

Stable angina

Answer 6

Healthy person
>increase in o2 demand is being met with increase in supply

Angina
>Atherosclerosis
>coronary arteries already partially occluded, decreasing supply
>arterioles dilate to make sure supply at rest is meeting demand

> problem occurs when PT becomes stressed or exercises
No coronary reserve because BV is already maxed out in terms of dilation, cannot supply more O2

Question 7

Stable angina - Aim of treatment

Answer 7

Treat to
>prevent attacks (prophylactic, but if attack occurs, we want to treat it ASAP because of the pain)
>relieve symptoms
>prevent progression to heart attack

Use drugs to
>increase O2 supply
>Reduce O2 demand

Question 8

Increasing O2 supply

Answer 8

Dilate coronary arteries
>under local metabolic control
>may be maximally dilated already
>difficult to dilate atheromatosus arteries

Reduce heart rate
(main way we go about reducing angina)
>heart spends longer in relaxation phase
>coronary arteries have longer to fill

Question 9

Decreasing O2 demand

Answer 9

Decrease cardiac output
>reduce heart rate
>reduce stroke volume

Reduce preload
>dilate veins, reduce venous return

Reduce afterload
>dilate arterioles, decrease resistance

Question 10

Stable angina - drug treatment

Answer 10

PRELOAD
>Nitrates
>used mostly to relieve an attack
>work by reducing preload

AFTERLOAD
>Ca2+ channel blockers

MYOCARDIUM
>Ca2+ channel blockers
>B-AR antagonists
>Ivabradine (relatively new drug that targets JUST heart rate because it has a unique target)

Question 11

Nitrates - Mechanism of Action

Answer 11

Drug undergoes biotransformation
(acted on by enzymes, actions of the enzymes release nitric oxide, cause dilation of vessels > mimicking a biological process)

> Releases NO
stimulates guanylate cyclase in vascular smooth muscle (enzyme that converts GTP to cGMP)
GTP converted to cGMP

> > Increase in cGMP leads to increase in intracellular calcium, leads to dephosphorylation in MLC (deactivated, cannot undergo crossbridge cycling)
Shifting balance to dephosphorylated MLC form, get less contraction, more relaxation, lumen is open
vascular relaxation

Question 12

Nitrates in angina - sites of action

Answer 12

Relaxation of all vessels
(main effect of this drug is on veins, bigger vessels are more affected by nitrates than small vessels)

Veins
>decrease preload (major dilatation, get reduced venous return)

Large arteries
>decrease afterload (small)

Coronary arteries
>no increase in flow with fixed stenosis
(arteries stiff, unable to dilate)
>no diversion of flow from ischemic area

Question 13

Nitrates in angina - Drugs

Short acting

Answer 13

Short acting
>Glyceryl trinitrate (GTN)
(1st pass metabolism)

> inactive metabolite so not given orally (if taken orally, nearly 100% metabolised)

> sublingual for acute attack, anticipation of effort
(to bypass the liver, can also take before exercise or stress to try and prevent an attack)

> Transdermal for prophylaxis
(releases GTN slowly so it produces a relaxation of the veins in a chronic fashion)

> I.V. for emergency
(try and quickly prevent the attack from developing into thrombus formation and heart attack)

> care needed with storage - adsorbed by plastic, unstable
(GTN unstable to light)

Question 14

Nitrates in angina - Drugs

Long acting

Answer 14

Longer acting
>isosorbide dinitrate
(1st pass metabolism)

> Isosorbide-5-mononitrate
(active metabolite)

> oral for anticipation of effort, or prophylaxis
(it is the metabolite which is active, we want it to be metabolised in the liver)

Question 15

Nitrates in angina - Adverse effects

Answer 15

Effects on other smooth muscle (off target effects that are clinically insignificant)
>brief relaxation of gut, airways
>not clinically significant

Headache, flushing (too much dilation of BVs)
>cerebral, head, neck arterial dilation

Postural hypotension
>venous pooling, particularly problematic in the elderly

Small reflex tachycardia (dropping BP too much)
>usually used in combination with B-blocker or non-selective calcium channel blocker (helps limit the reflex tachycardia)

Question 16

Nitrates in angina - Drug interactions

Answer 16

Potential problems if cGMP increases too much

Why is the combination of GTN and viagra potentially lethal?
>viagra is a phosphodiesterase inhibitor, stops breakdown of cGMP
>GTN causes increase in cGMP

Together, they reduce HR so low that it is potentially fatal

Question 17

Nitrates in angina - Tolerance

Need more and more of the drug to get same effect

Answer 17

Reduced effectiveness with continuous use via:

“classic” mechanism involves depletion of tissue thiols (enzyme) required for NO production from GTN
»treatment with N-acetyl cysteine restores GTN effect

Increased release of and/or sensitivity to constrictors
>e.g. Angiotensin II

Increased endothelial free radical production scavenging NO, reducing NO bioavailability

Reduced/abnormal activity of muscle mitochondrial ALDH2 (aldehyde dehydrogenase 2), decreased NO production, increased free radicals

Drug-free period required to minimise tolerance
>remove patch over night

> > take home message: miniminse exposure to GTN

Question 18

Beta blockers in angina - MOA

Answer 18

Mainstay for prophylactic treatment of angina
>this is because when you exercise or are stressed, you increase sympathetic drive
>increase in adrenaline, bind B1, increases contractility, increase CO, HR increase, heart work harder, need more O2 to prevent angina

Block effects of sympathetic nervous system on cardiac B1-ARs
1) SA, AV nodes
>reduce HR

2) Cardiac muscle
>reduce contractility, reducing work of the heart

3) reduce renin release, downstream effect of reduction in TPR

Result in
>increase diastole time
>increased coronary perfusion
>increased o2 supply

Question 19

Beta blockers in angina - drugs and adverse effects

Answer 19

First line therapy for prophylaxis

Adverse effects and contraindications
(all tied into blockage of adrenoceptors, talking about a continuum of selectivity, the higher the dose, the more likely you are going to be affecting other AR-subtypes)

1) Cold extremities
(blocking dilation of subcutaneous vessels)

2) Fatigue
(reducing cardiac output, muscles arent going to get perfused, also blocking dilation of skeletal muscle vessels B2-AR)

3) Cardiac depression, particularly in elderly
(reduce contractility = affect heart function)

4) Bradycardia
>can lead to life-threatening heart block in patients with coronary disease
(reduced HR)

5) Bronchoconstriction
>life threatening in patients with asthma or COPD
(B2-AR important in lungs, B2-agonists open up airways, if we used a B-AR blocker, has the potential, particularly in PTs with asthma or COPD, to block dilatation of airways caused by adrenaline)

6) Decrease symptoms of hypoglycaemia
>when BGL is low, one of the effects is release of adrenaline
>one of the main ways of monitoring hypoglycaemia is noticing tachycardia (increased HR) due to the adrenaline
>If you are on a beta-blocker, that tachycardia is going to be prevented = hypo unawareness

Withdrawal Syndrome (taper dose)
>need to prevent rebound hypertension
>when we block the receptors, we get an increase in receptor number
>when we remove blockage, there are more receptors there, have potential for rebound hypertension in these instances

Question 20

Sites of action of Ca2+ channel blockers

Answer 20

Block contractility of heart, block HR

Block influx of Ca2+ into these muscles, result in a number of effects

Block Ca2+ in cardiac myocytes = reduce contractility

Block in nodal tissue = increase HR

Block in coronary arteries = increase vasodilation, increase myocardial o2 supply

*Predominant effect of Ca2+ blockers is on arteriole side, not on venous side, will reduce afterload (increase vasodilation, reduce afterload, reduce myocardial o2 demand)

Question 21

Calcium channel blockers - drugs and selectivity

Answer 21

Non-selective L-type calcium channel inhibitors
>will have effects in heart and vasculature
>e.g. Verapamil and diltiazem

Vascular selective L-type calcium channel inhibitors
>will affect vessels (arterioles only)
>thats why they are good for hypertension, reduce TPR really well
>e.g. nifedipine

Question 22

Non-selective calcium channel blockers - mechanism

Answer 22

Heart effects
>block Ca2+ entry (nodal/conducting tissue, myocardium) through voltage-gated L-type channels
>decreased heart rate, increased o2 supply
>decreased HR, SV, CO, reduced demand

Vascular effects
>block Ca2+ entry into vascular smooth muscle cells through voltage-gated L-type channels
>Arterial dilatation, reduced afterload and demand

Question 23

Vascular selective calcium channel blockers - Mechanism

Answer 23

Vascular effects
>block Ca2+ entry into vascular smooth muscle cells through voltage-gated L-type channels
>arterial dilatation, reduced afterload and demand
>dihydropyridines most potent

> Nifedipine is really potent in terms of effects on vasculature

Question 24

Calcium channel blockers in Angina - Adverse effects

Non-selective (veraprmil & diltiazem)

Answer 24

Non-selective (veraprmil & diltiazem)

> flushing, headache, oedema
(oedema quite uncommon, one of the mian things that people are intolerant to when it comes to Ca2+ blockers, swelling around ankles because of change in pressure, change in arteriole dilatation but not met in venous side = leakage of fluid = oedema)

> bradycardia, atrioventricular (AV) block
(If we are using a drug that is causing cardiac depression and reduction in HR like non-selective Ca2+ blockers, we would never pair it with a drug that does the same thing (like a beta blocker) because that can cause too much cardiac depression, too much reduction in HR = fatal)

Question 25

Calcium channel blockers in Angina - Adverse effects

Vascular selective (nifedipine)

Answer 25

Vascular selective (nifedipine)
>flushing, headache, oedema
>hypotension (too much dilatation which causes Reflex tachycardia)
>Reflex tachycardia
>can be taken with B-blocker

Question 26

Calcium channel blockers in Angina - Adverse effects

Drug-drug interactions

Answer 26

Drug-drug interactions
>metabolism (verapamil & diltiazem) cytochrome P450 enzymes
(mild inhibitors of CYP450 family of enzymes - issue with other drugs that are metabolised this way)

> non-selective (verapamil & diltiazem) never taken with B-blocker or digoxin

Question 27

Novel therapy - Ivabradine

Answer 27

No reduction in contractility, no cardiac depression like you see with Ca2+ and Beta blockers

> “pure” heart rate reduction

> “specific” and selective inhibition of the inward sodium-potassium If current in the sinus node (unique “funny” current within the SA node)

> decreases the velocity of diastolic depolarisation by reducing the ‘steepness’ of the If current clope

> Reduces myocardial oxygen demand and maximises oxygen supply

Question 28

Ivabradine - MOA

Answer 28

Blocks influx of sodium into these cells in SA node (Na+/K+ channel)

Results in slowing of depolarisation, membrane potential isnt going to increase as quickly as it normally would

Depolarisation will cause electrical potential to transmit through the SA node (pacemaker activity)

With Ivabradine, we get less influx of sodium, steepness of depolarisation curve reduces

**Ivabradine mediated slowing of diastolic depolarisation

Question 29

Novel Therapy - Ivabradine

Answer 29

Used only if heart rate is > 70 BPM
(can reduce HR by 10-15BPM - quite a lot)

Adverse effects
>brightness in visual field due to retinal effects
(funny channel is also found in retina)
>bradycardia
>conduction abnormalities (same target and site)
(changes in conduction of HR)

Precautions
>HR <70BPM (dont want to get bradycardia)
>Levels increased by some antibiotics and antifungals
>non-selective Ca2+ channel blockers (verapamil and diltiazem)
(inhibitors of CYP450 - contraindicated when using Ivabradine)
(Ivabradine is also metabolised by CYP450 enzymes, be aware of drug-drug interactions)

Question 30

Notes on therapy

Answer 30

Nitrates, Ca2+ channel blockers, B-blockers are not disease modifying
>i.e. they dont change the outcomes
>unchanged risk of MI, sudden cardiac death, or all-cause mortality
>just trying to prevent symptoms from occurring or trying to treat the symptoms

Long term benefit of ivabradine to be determined

Combination therapy often required
>Prophylaxis to reduce frequency and severity, acute treatment to relieve symptoms
>maximise effects to increase supply, decrease demand
>minimise adverse effect (e.g. nitrates cause reflex tachycardia but atenolol or verapamil decrease HR)

**Often would be on GTN to reduce attack, and be on Ca2+ channel or beta blockers for prophylaxis
>benefits of using beta-blocker or non-selective Ca2+ blocker = reduces likelihood of tachycardia that you would see in GTN if used too much or dose too high

Question 31

Summary of stable angina treatment options

Answer 31

1) Ivabradine
>reduce HR
>increase O2 supply
>decrease O2 demand

2) B-blockers
>reduce HR
>reduce SV
>Increase o2 supply
>Decrease o2 demand

3) Ca2+ channel blockers
>reduce HR
>reduce SV
>reduce afterload (TPR)
>Increase o2 supply
>Decrease o2 demand

4) Nitrates
>Decrease preload (venous return)
>reduce o2 demand

Question 32

Treatment of variant angina

vasospastic form, not necessarily any occlusion of coronary arteries

Answer 32

Relieve coronary spasm using short acting nitrate
(arteries can dilate NOT due to partial occlusion)

Prophylaxis with dihyropyridine Ca2+ channel blockers (counteract vasospasm)
>adverse effects and contraindications as described

B-AR antagonists contraindicated
>vasospasm via a-adrenoceptor may be worse if B2-mediated coronary dilation blocked

Question 33

Treatment for unstable angina

Answer 33

As per classic angina

Also include low dose aspirin to prevent thrombosis

Question 34

Ongoing treatment

Answer 34

Want to prevent the worsening of these conditions in these patients
>like with all dyslipidaemia, all these help improve cardiac function
>we want to treat hypertension, dyslipidaemia, diabetes

Optimal medical therapy

Risk factor reduction and prevention
>stop smoking
>increase physical activity, lose weight
>treat hypertension, dyslipidaemia, diabetes

Revascularisation
(if frequency of attacks is too much, surgery may be an option based on the position of the stenosis)
>PCI - precutaneous coronary intervention
>CABG - coronary artery bypass graft