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The Pharmacology and Therapeutics element of the Cardiovascular System
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The Pharmacology and Therapeutics of the Cardiovascular System in pharmacy.
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CVS Pharmacology and TherapeuticsDyslipidaemia - Atherosclerosis and Lipid Lower Drugs
- Hypercholesterolaemia – elevated levels of plasma cholesterol (leads to cardiovascular
disease)
- Dyslipidaemia – derangements of the balance of lipids
- Both dyslipidaemia and hypercholesterolaemia are risk factors for atherosclerosis i.e.,
the build-up of focal lessons (plaques) on the inner surface of an artery, causing them to
harden
- Atherosclerosis leads to:
o Ischaemic heart disease (IHD) – poor blood flow that leads to angina/heart attack
o Peripheral vascular disease (PVD) – disease of arteries in legs
o Cerebrovascular disease – disease of blood vessels in brain
Risk factors for Atherosclerosis (cardiovascular disease)
- Genetic – family related
- Hypercholesterolaemia/dyslipidaemia – if there are high LDL (bad cholesterol) or lower
HDL (good cholesterol) levels
- Hypertension
- Obesity
- Smoking
- Hyperglycaemia
- Reduced physical activity
- Infection?
o BMJ 2010 - Poor dental hygiene is a risk factor; it can lead to low levels of
inflammation that contributes to atherosclerosis
o Some patients never or rarely brushed their teeth and they have a 1.7 x risk
o There was increased levels of C reactive protein
Drug-induced dyslipidaemia can be caused by:
- Beta blockers
- Thiazides
- Corticosteroids
- Retinoids – monitor lipid levels during treatment
- Oral contraceptives
- Anti-HIV drugs
Hypercholesterolaemia
- In terms of transport of lipids/cholesterol around the body we focus on lipoproteins
- Lipoproteins – central core of hydrophobic lipid, encased in phospholipid, cholesterol
and apolipoproteins
o HDL – high density lipoproteins; they absorb cholesterol from cell breakdown
and transfers it to VLDL and LDL in the liver (it is good because reduces
cholesterol in the body)
,CVS Pharmacology and Therapeutics
o LDL – low density lipoproteins; they are a large component of cholesterol, taken
up by the liver and tissues via endocytosis via an LDL receptor. It is associated
with atherosclerosis, and the transport of LDL damages the blood vessels
o VLDL – very low-density lipoproteins; these transport cholesterol and
triglycerides to the tissues where the triglycerides are removed leaving LDLs
- Chylomicrons – transport triglycerides and cholesterol from GIT to liver. Free fatty acids
are released and cholesterol is stored and oxidised to bile salts or released to VLDLs.
Hypertriglyceridemia is a modest risk factor of CVS disease
- Dyslipidaemia is a risk factor of atherosclerosis
- Rather than just the absolute level of cholesterol, we are more concerned about the
cholesterol levels in regards to other CVS parameters
- Ideal cholesterol level is <4.8mmol/L
- Hypercholesteremia is when triglyceride level exceed 6.5mM
- Xanthomata – yellow deposits in eyelids or wrists can indicate high levels of cholesterol
(physical sign)
Atherogenesis – an inflammatory response to injury
- The process by which atherogenesis occurs
- The inner surface of blood vessels is known as the endothelium, and beneath the
endothelium is the blood vessel wall
- In atherogenesis occurs as you age, or
expose yourself to risk factors (smoking,
reduced exercise obesity) and this damages
the endothelium
- This damage leads to an inflammatory
response that promotes vascular changes
known as atherosclerosis
- This diagram demonstrates this e.g., if
patient smokes, has hypertension and
turbulent blood flow this causes damage to
the endothelium.
- The LDL and its receptor is also shown here.
The LDL is transporting cholesterol around,
and the LDL receptor allows cholesterol to be
taken into cells (normal)
- As you get damage to the endothelium,
there will be infiltration in the site of damage with monocytes and macrophages (WBCs)
and this causes inflammation, which then releases reactive oxygen species (ROS), which
oxidise the LDL, causes damage to the LDL receptor causing abnormal cholesterol
deposition beneath the endothelium.
- At the age of 19-20, blood vessels are healthy, but as this age is exceeded, foam cells can
develop beneath the endothelium, which are cholesterol rich, as a result of this damage
- Cholesterol forms in the foam cells and they are known as fatty streaks
,CVS Pharmacology and Therapeutics
Plaque formation
- Overtime, the fatty streaks develop into a cholesterol rich plaque (yellow) which blocks
the blood vessels.
- This therefore causes the narrowing of the blood vessels
and symptoms of angina can start to show
- The plaque can be unstable and break apart, but this
leads to platelet sticking, resulting in a heart attack or stroke
Ageing of a blood vessel
- Initially we have healthy
endothelium (around the
age 19-20)
- As blood vessels start to
damage due to ageing and
other risk factors, there will
be deposition of foam cells
beneath the endothelium ,
leading to fatty streaks
- In time, there is the
formation of cholesterol
rich atherosclerotic
plaques, leading to the
narrowing of the arteries
and therefore symptoms of
ischaemia in angina
- If the plaque ruptures, this leads to platelet aggregation and clot formation and
occlusion of the artery
- The main aim of statins is to slow this process down
Management
Modify risk factors – lifestyle advice
- Stop smoking/smoking cessation
- Treat hypertension and diabetes – to reduce vascular damage
- Exercise
- Drug induced? – change drug
- Low cholesterol diet
o 75% of cholesterol in the body is made in the body – it doesn’t come from diet.
Having a diet rich in saturated fats is associated with causing a rise in LDL,
therefore causing dyslipidaemia (though only 25-30% of cholesterol comes from
diet)
Cholesterol synthesis
- The enzyme responsible for cholesterol synthesis is the HMG-CoA Reductase
- This enzyme, is the first enzyme in the first step of cholesterol synthesis
,CVS Pharmacology and Therapeutics
- It starts off with hydroxmethylglutaryl coenzyme A
reductase catalysing hydroxmethylglutaryl to form
mevalonate. In the end after several other steps,
cholesterol is formed
- HMG CoA reductase enzyme is the target for statins to
inhibit cholesterol synthesis
- This suggests that using statins will reduce cholesterol
synthesis by the liver
Statins
- E.g., simvastatin, pravastatin, atorvastatin*,
Fluvastatin (* NICE Recommended)
- Statins reduce plasma cholesterol
- The reduction in hepatic (liver) cholesterol
synthesis leads to the upregulation of
hepatic LDL receptors, promoting LDL
uptake into the liver, where the cholesterol
can be processed and excreted in the bile
- Overall, statins work by increasing the
uptake of cholesterol from plasma by the
liver
- Statins are less effective in homozygous
familial hypercholesterolaemia (atherosclerosis is developed from a very early age and
heart disease can be developed in 20’s. This is because the body cannot make LDL
receptors, so the LDL/cholesterol just sticks on blood vessels)
o Atorvastatin may be effective, but likely not to be in this case
o Statins are effective in heterozygous disease
- Because statins act in the liver, they are very hepatoselective
o Statins inhibit cholesterol synthesis in the liver
o The liver is the main site of cholesterol synthesis, extrahepatic sites synthesise
essential cholesterol
o Statins undergo extensive 1st pass metabolism, so only 5% reaches systemic
circulation (lowers side effect risk)
The effect of statins
- Some evidence suggests that statins lead to regression of atherosclerosis
- There may be lipid depletion, leading to the stabilisation of lesions
- Statins reduce the progression of carotid disease, and reduce risk progression of carotid
disease, and stroke
- Improve endothelial function?
Heart Protection Study (2002) – Lancet 360, 7-22
- This study found that by using 40mg of simvastatin in high-risk patients (CHD, stroke,
diabetes, hypertension) substantially (25%) reduced stroke/revascularisation in all
patients – even with low/normal cholesterols
, CVS Pharmacology and Therapeutics
There are three additional drugs to statins that are used if a patient has a heart attack to
prevent further events:
- Aspirin (or another antiplatelet drug)
- Beta blockers
- ACEI (ACE inhibitors)
- Each of these treatments independently and additively reduce the risk in secondary
prevention (75% total risk reduction)
The use of statins in treatment of hypercholesterolaemia, raised LDL, and atherosclerosis
- Population who may benefit is large
- Patients with CVD
- NICE 2014 recommended that the primary prevention is the use statins in patients
with a >10% risk of CVD over next 10 years
o Assess the risk using QRISK3
o 20mg atorvastatin – low intensity for patients who haven’t had a CV event
o Secondary prevention in patients who have had a CV event – 80mg atorvastatin
(high intensity)
- All statins, EXCEPT ATORVASTATIN, should be taken at night because that’s when most
cholesterol is produced in the body
- Atorvastatin has a much longer half-life, so it doesn’t need to be taken at night, it can be
taken at any time of the day
Adverse events (side effects) of statins
- Muscle pain (quite common)
o Very rarely, this muscle pain leads to rhabdomyolysis (breakdown of skeletal
muscle, myoglobin is released and the renal tubules become blocked.)
o Simvastatin > atorvastatin (this side effect is lower in atorvastatin)
o Counsel patients on this
- Increased diabetes but expert view suggest that this is outweighed by CVS benefits
- Nocebo effect – patient imagine/exaggerate their side effects
Clinical Pharmacology
- Before, and during statin treatment, monitor liver function (LFTs) due to the effects of
the statin on the liver
- Simvastatin is contraindicated with macrolides e.g., clarithromycin because they inhibit
the breakdown of simvastatin, raise its plasma conc and increase the risk of side effects
such as rhabdomyolysis
- Simvastatin has interactions with amlodipine, verapamil, diltiazem
- For amlodipine + statin:
o Pravastatin doesn’t interact with amlodipine
o If simvastatin must be used, use a 20mg as the max dose
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