Cardiovascular Disease & Risk Factors (5) Ischaemic heart disease Flashcards
- Appreciate requirements for cardiac blood supply based on cardiac demand (work) - Describe pathophysiology of IHD/angina - Explain rationale for the different drugs used in angina - Describe the MOA of drugs used to treat angina - Describe factors that may limit the usefulness of drugs used in the treatment of angina
Ischaemic Heart Disease
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
O2 supply of the heart
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)
O2 demand of the heart
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)
Angina Pectoris - Definition
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
Angina - Therapy varies with type
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
Stable angina
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
Stable angina - Aim of treatment
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
Increasing O2 supply
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
Decreasing O2 demand
Decrease cardiac output
>reduce heart rate
>reduce stroke volume
Reduce preload
>dilate veins, reduce venous return
Reduce afterload
>dilate arterioles, decrease resistance
Stable angina - drug treatment
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)
Nitrates - Mechanism of Action
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
Nitrates in angina - sites of action
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
Nitrates in angina - Drugs
Short acting
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)
Nitrates in angina - Drugs
Long acting
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)
Nitrates in angina - Adverse effects
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)
Nitrates in angina - Drug interactions
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
Nitrates in angina - Tolerance
Need more and more of the drug to get same effect
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
Beta blockers in angina - MOA
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
Beta blockers in angina - drugs and adverse effects
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
Sites of action of Ca2+ channel blockers
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)
Calcium channel blockers - drugs and selectivity
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
Non-selective calcium channel blockers - mechanism
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
Vascular selective calcium channel blockers - Mechanism
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
Calcium channel blockers in Angina - Adverse effects
Non-selective (veraprmil & diltiazem)
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)
