14. cardiovascular pathopharmacology

trauma (as simple as gravity over time) -> damage to valves

gradual venous distension

incompetent valves + ↑ Pressure -> edema

very common in veins of legs cuz gravity pulls on blood, which makes it accumulate and push on sides of veins

progress to chronic venous insufficiency - so much blood pools in veins that gas exchange become improper -> inadequate nurtrient supply -> venous stasis ulcers

thrombus = attached blood clot

thromboembolus = detached blood clot

embolus = thromboembolus blocking smaller vessel

thrombus in a deep vein

venous thrombus is more common than arterial

- higher risk of pulmonary embolism - after the veins, the blood goes to the right atrium (can't get stuck here) and then the lungs (can get stuck here) to get oxygenated

little to no clinical signs before embolus -> maybe edema if increased P

Virchow's triad

- hypercoagulability (can happen anywhere)

- endothelial injury

- venous stasis (can't send blood from legs to heart)

normally: stand up -> decreased venous return due to gravity -> decreased BP -> baroreceptor reflex (FAST) -> ↑ SNS -> ↑ BP

defective baroreceptor -> drop in BP upon standing is not compensated for adequately

1. acute temporary factors: drugs, stand up immobile (venous pooling), huge diuresis

2. chronic: primary or secondary: metabolic syndrome, cardiovascular autonomic neuropathy

prevention: raise slow, calf raises, vasoconstrictors

similar to vein thrombosis -> abnormal coagulation initiation

- often caused by abnormal clotting factor activation or presence of an atherosclerotic plaque

major risk factor

- atherosclerotic plaques, valvular diseases, aneurysms

- septic shock -> systemic inflammation -> multiple micro-vasculature thrombi via immune system which activates clotting factor -> tends to happen in micro vessels

complications

- tissue ischemia + necrosis

- systemic thromboemolus: block blood and O2 from reaching downstream organs

Tx

- ballon angioplasty: semi-invasive surgery -> insert catheter then open balloon and clear vessel

piece of thrombus detaches, travels then blocks a vessel

venous embolus block pulmonary vessels -> pulmonary embolism

arterial embolus clog systemic vessels -> MI and stroke

Ischemia downstream of embolus -> tissue necrosis -> sepsis

- coronary occlusion -> myocardial ischemia

- cerebral artery occlusion -> stroke

thromboembolus -> I.e. atria fibrillation

air embolism -> room air via IV, ensure no air in needles

amniotic fluid embolism -> increased pressure during delivery

bacterial -> clump dislodging following endocarditis

fat -> skeletal trauma releases fat globules

foreign matter -> glass, drugs

localized distension/dilation of vessel wall

- caused by excessive tension in blood vessel wall

- more common in art + thoracic arteries (high BP + radius)

common causes = chronic HTN + atherosclerosis

- weakening of vessel wall and/or increased BP -> increased wall dilation

fusiform circumferential: equal distension all around

fusiform saccular: distension on one side

false: rupture + clot

dissecting saccular: only outer membrane bulges, small breakage of inner membrane, pocket fills with blood and can coagulate inside

aortic dissection

risk factors: atherosclerotic plaques or trauma

more likely in aorta because tension on vessel is proportional to BP + radius -> aorta has greatest BP + radius, so greatest tension, so huge risk for aneurysm

small vessels in brain are commonly observed to have aneurysms due to tension being inversely proportionate to the wall thickness

Cerebral blood flow = amount of blood flow going to brain, adjusted based on metabolic needs/demands (decreases while asleep)

cerebral blood volume = total amount of blood in cranial cavity, affected by CBF but takes into account what was already there, including CSF

Cerebral perfusion pressure = MAP - intracranial pressure

- CBF = CPP/ cardiovascular resistance

- increased intracranial pressure leads to vasodilation -> edema -> increased CBV

1. inadequate cerebral perfusion (low CPP, ex: pt has hypotension, so not enough pressure to pump blood to brain)

2. normal CPP but increased intracranial pressure (ex: MAP-ICP = 120 (high) - 50 (high) = 70 (normal))

3. cerebral hyperaemia (high CBV - way too much blood in cranium -> increases local pressure)

CPP = 70 mmHg

intracranial pressure = < 20 mmHg

MAP = 90 mmHg

increased intracranial pressure (normal 5-15 mmHg)

causes

- increased content in brain cavity (tumor, CSF)

- brain hemorrhage

- cerebral edema

-> there is only one opening at spinal cord -> this is protective but if problems are coming from within its a problem

when ICP goes up, CSF will be displaced out of cranium to compensate, but if ICP still high after this CBF and CBV alterations will occur

its a cycle

increase in edema and tissue pressure -> increased ICP -> decreased CPP -> decreased CBF -> increase in ischemia -> dysregulation of compensatory mechanisms -> increase in edema and tissue pressure

ICP starts to increase

stays low due to compensatory vasoconstriction

mental status: A+O x3

pupils: equal + reactive

breathing: normal

BP: normal

Pulse: normal

temp: patterns vary

Sx worsen since compensation is insufficient

systemic vasoconstriction to compensate for elevated ICP -> trying to push blood into brain

mental status: confusion, restlessness, fatigue

pupils: equal + reactive

breathing: normal

BP: normal

Pulse: normal

temp: patterns vary

ICP approaches arterial pressure

becomes impossible for heart to pump blood into brain

brain hypoxia + hypercapnia (high CO2)

rapid deterioration, loss of autoregulation

drastic rise in ICP -> increased CBV -> BIG ICP drop -> severe hypoxia + hypercapnia

acidosis

mental status: inability to stay awake

pupils: small reactive

breathing: may slow

BP: systolic increase, diastolic decrease

Pulse: drops, bounding

temp: patterns vary

herniation stage

mental status: coma

pupils: bilateral dilation

breathing: hyperventilation, ataxic

BP: systolic increase, diastolic decrease

Pulse: drops, bounding

temp: patterns vary

brain tissue moves from high pressure environment to low pressure environment

compression of normal areas

increased ICP even further than systolic

CBF = 0

neuronal death

Sx depend on compressed areas (ex: occipital -> vision bye)

1. vasogenic: most common

- brain injury -> increased capillary permeability (loss of BBB) -> protein + fluid leakage -> increased ICP

- self promoting cuz increased ICP produces more edema

2. cytotoxic of metabolic: no disruption of BBB

- toxic molecules (drugs/poison) impair active transport -> K+/Na+ mismatch -> cell swelling

3. interstitial: often caused by noncommunicating hydrocephalus

- CSF leaks through ependymal cell layer around ventricles

accumulation of CSF- example of cerebral edema

1. communicating

- malabsorption of CSF at arachnoid villus (location where CSF is reabsorbed and put back into venous circulation)

- blockage here means CSF accumulates and can't get into venous circulation

2. noncommunicating

- obstruction of CSF flow to arachnoid villus -> creates a void

- CSF downstream from obstruction gets absorbed into venous circulation, but pressure build up behind obstruction

- once ICP increased, compression will go towards empty void

ventricle dilation -> increased CSF pressure -> leakage -> interstitial edema -> compression of brain areas proximal to ventricles -> increased ICP

often develops progressively

acute hydrocephalus = EMERGENCY

normal pressure hydrocephalus = no increased ICP

any brain abnormality caused by vessel disorder

- ex: strokes + brain aneurysms

something blocks blood to brain - FAST acronym

classified by pathology:

1. ischemic stroke (embolus/thrombus) -> most common

2. global hypoperfusion (occurs w/shock)

3. intracranial hemorrhage (vessel isn't blocked, but not enough blood can reach the target)

hypertension = greatest risk factor

- others: intercranial atherosclerosis, dyslipidemia, diabetes

range of outcome: complete recovery to coma/death

caused by clot -> obstructs blood to brain

atherosclerosis -> cerebral thrombus -> thromboembolus -> embolus -> stroke syndrome = cerebral infarction

thrombotic stroke -> thrombus from cerebral circulation

embolic stroke -> thrombus from systemic circulation

cerebral infarction = area of brain deprived of blood supply -> Tx is to restore blood supply; brain matter may be irreversibly damaged within 20 mins; ishemic area -> necrosis

remember reperfusion injury!

damage to vessels, blood starts to accumulate around brain matter

still some necrosis but less cuz there is some O2 and glucose diffusion, but it is suboptimal

higher chance of ICP than ischemic stroke

manifestations depends on affected brain area

- recovery is better w/fast intervention

- prognosis > ischemic stroke

potential consequences

- IICP -> herniation

- decreased CBF and hypoperfusion

- cerebral edema

often occur following ruptured aneurysms

associated w/massive headaches/unconsciousness

aneurysm = blood vessel bulging out cuz of increased pressure + weakening of endothelial cells

IC aneurysm are most likely in circle of Willis -> cuz of design, twists, turns -> blood bumps + rubs on vessels a lot and can cause damage

hypertension + flow disturbances -> general weakening + abnormalities within vessel wall

most often asymptomatic until ruptured

- surgical management = best prevention

- rupture causes = trauma, excessive BP

ruptured aneurysm -> intracranial or subarachnoid hemorrhage -> rapid Sx onset

classified based on shape

berry aneurysms = most common, internal layer is broken but outer layer still holds

often follows ruptured aneurysm -> hemorrhage -> inflammatory reaction + chug arachnoid villi and ventricles (hydrocephalus) -> increased ICP -> decreased CPP + CBF

acts like space-occupying lesion -> compresses neural tissue (herniation) - since this is subarachnoid space, it can wrap around brain + block all exits + compress inwards

80% of pt show infarction on MRI -> 50% survival rate

deficits depend on location + intensity of bleeding

- common = motor, speech, vision

mild leak = episode headaches + alterations of mental status

sudden rupture -> explosive headache -> nausea + vomiting

rebreeding = greatest risk -> mortality up 70%

classified on a scale depending on manifestations

coronary artery disease (CAD) - when coronary artery is obstructed

myocardial ischemia (MI) - when obstruction is bad enough to cause an intermittent imbalance between supply and demand, comes with angina

acute coronary syndrome (ACS) - heart attack, occurs when complete block of supply

process in which deposits of fatty material (plaque) build up inside walls of arteries -> reduces/blocks blood flow

exact cause is not clear

hypothesis: damage to endothelium

substances in blood (fat, cholesterol) accumulate inside damaged area -> chemical reactions inside build up cause cholesterol to oxidize -> initiates inflammatory response -> endothelial cells signal for help -> macrophages eat cholesterol -> become plaque

smooth muscle cells in arterial wall multiply and cover plaque (fibrous cap)

- over time this cap may break open -> releases plaque into bloodstream -> can form blood clot !

muscle heart tissue death from lack of blood flow

when coronary circulation blocked = heart attack

all heart attacks due to endothelial cell dysfunction -> damaged areas become site for atherosclerosis

plaque are constantly under stress from blood flow, small plaques break off

- the inner cheesy layer of plaque is thrombogenic -> tends to form clots very quickly

- platelets flow by and attach to exposed inner contents + pile up

- happens very quickly and artery is fully occluded

left anterior descending -> supplies anterior wall + septum of left ventricle

right coronary artery-> supplies posterior wall + septum + capillary muscles of left ventricle

left circumflex artery -> supplies lateral wall of left ventricle

- zone of perfusion = area that artery supplies w/blood

- most MIs are in left ventricle

NSTEMI: subendocardial (partial) infarct

- damage limited to inner third of endocardium

- <40 mins

- causes: short MI that is suddenly cleared (HTN, atherosclerosis)

- ST segment depression/ no ST segment elevation

STEMI: transmural infarct (whole wall) infarct

- damage to entire wall thickness

- 3-6 hours

- elevated ST-segment on ECG

- chest pain/pressure -> left arm or jaw referred pain

- diaphoresis (SNS response)

- nausea

- fatigue

- dyspnea

3 kep proteins

·      Troponin I

o   Elevated within 2-4 hrs after MI

o   Peak at 48 hrs

o   Stay in blood stream for 7-10 days

·      Troponin T

o   Elevated within 2-4 hrs after MI

o   Peak at 48 hrs

o   Stay in blood stream for 7-10 days

·      CK-MB (Creatine Kinase M + B)

o   Elevated within 2-4 hours after MI

o   Peak at 24 hours

o   Stay in blood stream for 48 days

§  Useful to diagnose reinfarction

·      2^nd infarction after 48 hours but before troponin levels go back to normal (<7-10 days)

o   Occurs following 10% of MIs

o   Arrhythmias

§  Highest risk in first 24 hrs after MI

§  Damage can disrupt how electrical signals are conducted

o   Cardiogenic shock

§  Heart can’t pump enough blood

§  Highest risk in first 24 hours after MI

o   Pericarditis

§  Inflammation of pericardium due to circulating neutrophils

§  1-3 days post MI

o   Myocardial rupture

§  Macrophages invade the tissue, healing process begins with formation of granulation tissue (yellow and soft)

§  3-14 days

o   Heart failure

§  Csrdiac tissue scarring process finishes

§  Scar tissue (greyish-white) doesn’t help pump blood

§  Other heart tissue tries to overcome but is not able to

§  After 2 weeks

o   Fibrinolytic therapy

§  Immediately following MI

§  Medications used to break down blood clots

o   Angioplasty

§  Minimally invasive

§  Deflated balloon inserted and then inflated to open artery

o   Percutaneous coronary intervention

§  Stent is placed in artery to physically open up the artery

all aim to increase blood flow

o   Antiplatelets – aspirin

o   Anticoagulants – heparin

o   Nitrates

§  Relax coronary arteries

§  Lower preload

o   Beta blockers

§  Slow heartrate and thus cardiac demand

o   Pain medication

§  Relieve discomfort

o   Statins

§  Improve lipid profile

happens due to re-established blood flow

influx of Ca++ -> stimulates the irreversibly damaged cells (and all other cells) to contract -> since they have been irreversibly damaged, they stay contracted and can’t relax -> in histology, we see contraction band necrosis

Influx of O2 can lead to more cellular damage -> conditions in an ischemic heart convert O2 into more ROS  -> damage more heart cells

atherosclerosis = gradual thickening and hardening of arterial vessel due to plaque buildup + inflammation

CAD = atherosclerosis of coronary arteries (subset of atherosclerosis)

same as atherosclerosis

development begins early in life -> impacted by genetics + lifestyle

proceeds gradually

accelerates as we age based on genetics/lifestyle/environment

clinically silent for decades

- you may feel in top shape, but can still have this happening

fatty streak composed of foam cells (lipid filled macrophages - they have ingested cholesterol)

plaque formation via smooth muscle cell hyperplasia

- smooth muscle cells proliferate and try to cover the foam cells

1. ApoB lipoproteins (LDL) get stuck within sub endothelial space

2. stuck LDL are oxidized (LDL-Ox) by ROS

3. phagocytosis of LDL-Ox by macrophages forming fatty streak

4. smooth muscle cells form a fibrous plaque around fatty streak

5. calcification of plaque

6. CVE/CVD

LDL and HDL are cholesterol (good + bad)

Subendothelial space = the space just beneath the single-cell layered endothelial layer; just underneath the space is the layer of smooth muscle

-       ApoB lipoproteins easily accumulate in this space

-       HDL (APoA):

o   Easily slip in and out of subendothelium

o   Atheroprotective → ‘Good’

-       LDL (APoB)

o   Tend to get stuck in the subendothelium

o   Also includes VLDL, IDL & Lp(a)

- atherosclerotic -> "bad"

Self-Promoting Atherosclerotic Cascade:

-       LDL tends to get oxidized by ROS

o   ROS is present under conditions of stress (even small amounts of stress)

o   Then the presence of the LDL causes further stress

-       Inflammation + ROS → LDL-Ox

-       LDL-Ox remain stuck + attracts LDL & macrophage

-       More LDL-Ox, etc.

-       When the LDL is oxidized, they get even more stuck, which leads to more oxidation, more inflammation -> vicious cycle

-       Foam Cell = Macrophage filled with LDL-Ox

-       Fatty Streak = Foam Cell Accumulation

-       Macrophages arrive and try to eat up the LDL

-       They become so full of LDL and can’t leave, they become foam cells and accumulate

1)    Protect endothelial integrity

-       Reduce  endothelial damage

2)    Anti-Oxidant

-       Reduce LDL-Ox

3)    Anti-Inflammatory

-       Reduce Macrophage & ROS that enter the area

4)    Delipidation

-       Remove cholesterol from foam cells and bring it back into the circulation and to the liver for metabiolism

Attempt to mitigate plaque stenosis. – the cap tries to push the accumulation of foam cells back down so that it is not occluding the blood vessel

-       Can work for a while but progression will resume if risk factors persist

-       3 mechanisms:

1)    Smooth Muscle Hyperplasia

-       Increase in the # of muscle cells and forms the cap

2)    Metaplasia into fibroblast

-       Fibroblasts = scar tissue that are very resistant and resilient, but do nothing else

-       lose the contractility that the smooth muscles have

3)    Secretion of collagen matrix

-       Each step continuously happens, so they keep piling up

Yet another attempt to mitigate plaque stenosis (narrowing of BV) progression.

-       Indicative of significant vasculature damage

-       Detectable via CT Coronary Calcium Score

o   Positive score suggests plaques are present at various stages in other locations

§  If u see calcification in 1 blood vessel, it’s pretty much impossible that it’s the only one

§  There are a few places in the body that we know tend to get damaged, so we look there first

The actual event

-  1st time we realize there is issue cuz we have clinical manifestations

#1 = Unstable plaque rupture

-       Direct vessel occlusion or indirect via clot formation

-       Indirect -> massive clotting response occludes the blood vessel

-       Either way, this is a sudden event

#2 = Stable plaque stenosis progression

-       the plaque slowly builds up

-       ASCVD Continuum! May remain silent for years until greater demand for blood supply

2.0 = where we are now, we have a lot of good drugs but we are very reactive -> good at prolonging life with disease

3.0 = preventative medicine -> improve QoL, prolong life withOUT disease

1)    Cardiovascular Disease

-       #2 Killer of Canadians (17.7% - 2021 Stats)

2)    Cancer

-       #1 Killer of Canadians (26.6%)

3)    Dementia / Alzheimer’s

4)    Metablolic Sybdrome and T2DM = Overarching RF that leads to 1-3

-       #1: LDL = ‘Bad’ Cholesterol’ – HDL = ‘Good’ Cholesterol

-       #2: Dietary cholesterol = crucial role in ASCVD Pathophysiology

-       #3: ASCVD happens almost exclusively to ‘old’ people/elderly

Problem: Simplistic & innacurate description

-       Ex.: They frequently exchange material between one another (eg. HDL can remove lipid from foam cells – does this then make the LDL good and the HDL bad?)

-       Does the cholesterol suddently become ‘good’ or ‘bad’ post-exchange?

Lipoproteins

-       Cholesterol is bound to lipoproteins (HDL - Apo-A,  LDL - Apo-B100)

-       It is not the cholesterol that matters, it is the lipoprotein that matters

-       HDL is good not because it’s HDL, it’s because it’s boudn to Apo-A

-       LDL is bad not because it’s LDL, it’s because it’s bound to Apo-B

Lipid Transport & Homeostasis

- Lipoproteins for Lipid Transport

•       Chylomicrons → transports Intestinal Fat to Liver

•       VLDL, IDL, LDL → transports fat from the Liver to Tissues

•       HDL → Circulation of fat to Tissues & back to the Liver

•   The lipoprotein is what drives the direction of the transport.

•       Apo-B binds to VLDL, IDL and LDL and drives transport to the tissue

•       Apo-A binds HDL and drives transport to the liver

-       Apo-A is a causative factor

-       We now know that how much atherosclerosis that someone has, is because of how much Apo-B they were exposed to in their life

#1 : total exposure to atherogenic particles (total apoB concentration x time)

- more important that total cholesterol

- analogy: 100 trucks carrying 100 tons vs 10000 scooters carrying 1 ton

- we are not worried about how bad damage is, we are worried about how likely damage is to happen, which is why exposure matters

#2: anything damaging endothelium

- ex: smoking (chemical damage), HTN (physical damage)

- triggers atherosclerosis cascade

- inflammation + ROS

- raises likelihood of stuck apoB

- increased space for accumulation

Problem: Vast majority of blood cholesterol is endogenous (i.e: non-dietary)

o   Heavily recycled and do not need dietary cholesterol

-       Most dietary cholesterol is excreted as feces and does not make it into the blood stream

-       Exception: Very large quantities of saturated fats CAN raise concentration of apoB lipoproteins

-       Why this misconception?

o   Rabbits are used for research, and rabbits (and chicken) absorb high amounts of dietary cholesterol and form atherosclerotic plaques.

o   We then extrapolated to humans…

o   We’ve known this for quite some time, Ancel Keys stated in 1952 that cholesterol is not a nutrient of concern for overconsumption’ (the USDA only stated this in guidelines in 2015)

Problem: Many cardiovascular events occur before 65:

-       Males = 50% / Females = 33%

-       In a paper, looking at autopsies of young people who died of other issues (eg. Car crash): 33% of 16-20 years old have visible atherosclerotic plaques or lesions (ex.: fatty streaks, calcification)

- Measures calcified plaque in the coronary arteries.

- Higher score = Higher risk of future cardiac events.

- Most routine

- Limitation vs. CT Angiogram:

o   Inability to detect non-calcified plaque

o   Later detection of Atherosclerosis (step #5)

- Specialized CT scan that captures detailed images of the coronary arteries allowing physicians to evaluate blood flow and identify any narrowing or blockages due to plaque build-up.

- Superior at determining risk of Major CVE vs CT Calcium Score

o   Can detect step #4 – earlier

o   Thanks to earlier detection of Atherosclerosis (step #4)

§  Some people form plaques, but they don’t get calcified

- Limitations

o   Uses IV dye contrast

o   more radiations + $$

- Rare and lesser known type of apoB particle – LDL fused with apo(a) lipoprotein

o   Has an extra ApoA bound to it with a little ‘scoop’

- Apo(a) = Multiple ‘kringles’ can trap cholesterol (especially LDL-Ox)

-  Evolutionary benefits? →  Sweep dysfunctional or ‘lost’ molecules back to liver

o   Back when we would eat when we could but then not eat for a long time

o   Now that we have high access to food, this is problematic

1) Highly Atherogenic:

o   apoB → get stuck in subendothelial space!

2) Pro-thrombotic:

o   increases risk of plaque rupture/significant stenosis

Most important and prevalent hereditary risk factor for CVD & aortic valve stenosis

o   There is NO modification of this via lifestyle

- Screening: One-time genetic test! ($20)

o   Who?: Ideally everyone

§  ≈20% have 100x ‘normal’ amount – we would consider these people to be at high risk

o   African-American heritage  predisposed to have high amounts vs Caucasian

-  Family history of premature CVD → Test ASAP!

Can’t do much about the Lp(a) itself, but remember that the reason it’s bad is because it brings the ApoA and ApoB with it (the ApoB is bad)

§  So we can use interventjons to aggressive ↓↓ apoB (↓ overall CVD risk)

Can we directly decrease Lp(a)?        

o   Diet & exercise → No impact

o   Certain Drugs → Yes (ex.: PCSK9 Inhibitors / ASOs)

§  No evidence it translates into CVD reduction

1)    Failure to appreciate the causative importance of total apoB burden

-  Must aggressively reduce it to truly reduce ASCVD risk

2)    Little knowledge regarding role of more rare but significant risk factors

-  Eg. Lp(a) – it is rare, but has a big impact

3)    Failure to grasp the lengthy time course of atherosclerosis development

- Benefits of acting early and aggressively compound over time

- Strategy should be akin to cigarette smoking: reduce exposure as much as possible ASAP

-  We can see the person headed for the cliff, why don’t we stop them sooner??

Healthy eating

·      Favor monounsaturated fats (ex.: avocados, macadamia nuts, olive oil)

·      Main benefits from eating healthily is a decrease  in triglyceride concentration & insulin normalization

·      Both can favor BP normalization ApoB decline & potency of Rx

·      Minimize saturated fats (can reduce LDL-R expression, which take LDL out of the circulation)

Activity

- 150 mins/week

Smoking cessation

statins

cholesterol absorption inhibitors

PCSK9 inhibitors

EPA

BAS

Nicain

benefits

·      ↓ LDL-C/ApoB

·      Also some evidence of anti-inflammatory effects

uses

·      ASCVD prevention (primary & secondary)

·      Hypercholesterolimia/Dyslipidemia (familial or behavioral)

·      Benefits proportional to ↓ LDL-C (apoB)

·      Many known & potential benefits under study for:

      - Metabolic Disorders (ex.: Diabetes)

      - Neurodegenerative Diseases (ex.: Alzheimer’s disease & MS)

     - Prevention of Cancer, Hepatic & Renal diseases

High-intensity therapy

·      Daily dose lowers LDL-Cholesterol on average by >50% (atorvastatin 40-80 mg, rosuvastatin: 20 mg)

Moderate-intensity therapy

·      Daily dose lowers LDL-C on average by 30-50% (Atorvastatin 10 mg, Rosuvastatin 10 mg, Simvastatin 20-40 mg, Pravastatin 40 mg, Lovastatin 40 mg)

All Statins have the same MoA

- HMG CoA-reductase inhibitors

· HMG-CoA is the rate limiting enzyme in the de novo synthesis of cholesterol

· Ultimate result is our cells produce less intrinsic cholesterol

· So the cells need to find cholesterol elsewhere

· Cells increase production of LDL-Receptors

· Cells then capture whatever LDL they can find in the circulation (this is good!) and uptake them

· Affects the VLDL as well

·  Reduces the export of VLDL from the cell (this is good, because it’s also apoB)

all PO available

Some are metabolised by CYP3A4 -> can impact your decision as to which statin to use

-       Consider renal and hepatic impairment on drugs

-       Rosuvastatin and atorvastatin are the preferred statins because they have the greatest effects

there is a table in slides

well tolerated →  Benefits > risks -> Resolve when discontinue

-       Myopathy/Rhabdomyolysis

-       Severe Myalgia

-       Fatal rhabdomyolysis  

Risks:

-       Old / Comorbidities

-      frequent with Rosuvastatin

-       genetic predisposition

Hepatotoxicity

-       stop if Serum transaminase levels up 3x

T2DM

-       Most likely = Ator / Least = Rosu

-       Discontinue if hyperglycemia

•       Cholesterol synthesis increases at night

•       Best to admin once daily in the evening to increase efficacy

• Drug concentration will be highest when it’s needed the most

Drug Interactions

•       Increased Adverse risk with other Lipid-lowering drugs → Increase Monitoring frequency

•       CYP3A4 inhibitors/inducers alter concentration of lovastatin, simvastatin & atorvastatin

Favor Rosuvastatin when possible

•       Most potent LDL-C/apoB decrease & minimal CYP3A4 interaction

•       Available generic (PMS-Rosuvastatin) → Cheaper

Reduce Rosu dosage in patients of Asian heritage

•       Because there seems to be a genetic link -> higher propensity for rabdo

•       Atorvastatin preferred for kidney disease patients (doesn’t require adjustments)

pregnancy

•       Teratogenic risk > Benefits (there are alternatives!)

•       Cholesterol = Crucial for hormone & cell membrane synthesis and development of neural connection and development → Crucial for fetal development

•       This is a relatively short discontinuation ( 9 months)

•       Fine in breastfeeding (ish) -> would depend on the risk of the patient vs the risk to the baby

-       2^nd most effective drug for lipid management (statins best)

-       Monoclonal antibodies

-       Normally, PCSK9 is a protein that degrades the LDL receptors (part of the normal recycling of the LDL receptors) -> means that LDL is not taken up into the cells an remains in the blood

-       PCSK9 inhibitors blocks the degradation of the LDL receptors so they can take LDL up into the cells

uses:

o   Combination with statins: Most potent approach to lowering ApoB (LDL-C) levels

o   Monotherapy: reduce LDL-C  ≈ Statins

§  We don’t use them as much as statins because they are newer (also possible other side effects)

o   Great option for statin-intolerant individuals

o   Only Rx capable of decreasing Lp(a)

§  If this is the patient’s specific problem, this is the best med

kinetics: subcutaneous (not PO cuz proteins so would be digested)

adverse effects:

- hypersensitivity reactions

- risk of anti-PCSK9 inhibitor antibodies production

NO drug interactions

- Recent Acute Coronary Event (ACS)

- Clinically evident ASCVD and any of the following:

o   T2DM

o   Polyvascular disease (vascular disease in >2 arterial beds)

o   Syptomatic PAD

o   Recurrent MI

o   MI in the past 2 years

o   Previous CABG surgery

o   LDL-C > 2.6 mmol/L or heterozygous FH

o   Lipoprotein(a) (Lp(a)) > 60 mg/dL (120 nmol/L)

- Cholesturamine, colesvelam, colestipol

- On the Canadian guidelines but there is unclear efficacy data and we have better options (Ex.: Ezetimibe)

o   Not recommended

MoA:

o   Inhibition of bile acid absorption -> increase cholesterol requirement -> increased LDL receptor expression -> decreased blood LDL concentration

-   Mild effect, mild adverse events

Therapeutic Use

o   Excellent when combined with Statins

§  Statins block cholesterol synthesis, so usually the body compensates by increasing billiary cholesterol reabsorption, but we don’t want this, we want the body to take it from the circulatiing LDL

§  So blocking reabsorption = synergistic effect with Statins

o   Mitigates reflexive increase in biliary cholesterol reabsorption

Adverse Effects

o   Very well tolerated

§  Common cold symptoms, arthralgia & diarrhea (gi upset)

o   Lower VLDL and triglycerides

o   Activation of PPAR-alpha receptor -> increased LPL synthesis + activity -> increased VLDL clearance -> decreased TG levels

Use

o   Most effective for TG decrease (little effect on LDL)

o   3^rd-line for ASCVD prevention/lipid disorders

o   Best combined w/dietary intervention

o   single out tryglicerides

o   good for pt with problematic triglyceride levels, and less of problem with apoB/LDL

Adverse

o   well tolerated

o   ↑ Gallstone risk

o   Possible myopathies & hepatotoxicity (like statins) -> don’t combine with statins

Interactions

o   Avoid Statin combination (↑ Rhabdomyolysis risk)

o   Displaces warfarin from albumin → Monitor coagulation if on both

Action: ↑ Triglyceride (TG) clearance from circulating VLDL particles & ↓ VLDL-TG synthesis and/or secretion

-       Result: ↓ blood TG → ↓ApoB

-       Uses: Patients with TG levels ≥ 1.5mmol/L already on maximal statin dose

-       Adverse Effects: Arthralgia

-       Action: Inhibition of hepatic DGAT2 enzyme

-       Result: ↓ TG synthesis → ↓ApoB

-       Uses: Recent evidence suggest poor risk-benefit ratio. Should be a last resort option

-       Adverse Effects: GI discomfort

-       Do not combine with Fibrates