cardiovascular system current treatments Flashcards
how many deaths worldwise are attributable to cardiovascular disease
approx 1 in 3
best prevented through lifestyle changes
what is CVD
multifactorial with risk factors including hyperlipidaemia, hypertension, obesity
drugs used to treat CVD - (5)
anticoagulant drugs
lipid lowering drugs
angina treatments
antihypertensive drugs
heart failure
examples of anticoagulant drugs
aspirin, warfarin, clopidogrel
example of lipid lowering drugs
statins
example of angina treatments
nitroglycerin
examples of antihypertensive drugs
beta blockers, calcium channel blockers
examples of heart failure drugs
digoxin, amiodarone, candesartan, captopril
where does digoxin come from
foxglove plant
what do most CVD trugs target
the adrenergic GPCRs
aka adrenoreceptors
what are adrenergic receptors endogenously activated by
adrenaline/ epinephrine
noradrenaline/ norepinephrine
adrenoreceptors can be divided into two groups. what are they called
alpha adrenoreceptors
beta adrenoreceptors
alpha adrenoreceptors are subdivided into two groups. what are they called
alpha 1 and alpha 2
alpha 1 adrenoreceptors are ____ ____
Gq linked
interact with PIP2, increase PKC, CamK2
alpha 2 adrenoreceptors are ____ ____
Gi linked
dec cAMP
beta 1-3 adrenoreceptors are ____ ____
Gs linked
stimulate cAMP
adrenoreceptors have differential expression and function based on
where they are expressed
alpha 1 adrenoreceptors in smooth muscle
constrict blood vessels and bronchi
beta 1 adrenoreceptors in the heart
inc heart rate and force of contraction
beta 2 adrenoreceptors in the heart
increase heart rate and force of contraction
beta 2 adrenoreceptors in smooth muscle
dilate blood vessels and bronchi
in the heart, activation of beta 1/2 adrenoreceptors
increase levels of intracellular cAMP as they are Gs linked
inc PKA intracellularly
in the heart, activation of beta 1/2 adrenoreceptors causes inc PKA intracellularly. what does this cause
activation of ryanodine receptor 2 (RyR2) and L-type calcium ion channel (LTCC)
release of calcium activates calmodulin
this activates myosin light chain kinase MLCK
MLCK can phosphorylate myosin filaments (interaction between myosin and actin is phosphate dependent, allowing for contraction)
where is the ryanodine receptor 2 (RyR2) located
sarcoplasmic reticulum
where is the L-type calcium ion channel (LTCC) located
on the cell membrane
beta blockers
beta adrenoreceptor competitive antagonists
bind to orthosteric site
examples of beta blockers
propanolol
beta 1 selective beta blockers
what is propanolol
non selective antagonist, so interacts with both beta 1 and beta 2 adrenoreceptors - binds to all in the body i.e. in lungs too
beta 1 selective beta blocker examples - 3
are cardioselective:
atenolol
bisoprolol
metoprolol
what are beta blockers used to treat
angina, heart failure, atrial fibrillation, after heart attack, tachycardia
recently, propanolol used as anti anxiety med to control inc heart rate symptoms
tolerability of beta blockers
generally well tolerated
but, dose dependent side effects inc low blood pressure causing postural hypotension at high doses esp in elderly patients
propanolol is a non selective beta blocker. what does this mean clinically
should be avoided in asthmatic patients as they prevent bronchodilation
asthma patients treatment
cardio selective beta blocker - only affects B1 receptor so doesnt impact B2 binding of SABAs
atherosclerosis
ateries become clogged with fatty substances called plaques or atheroma
plaques harden and increase risk of blood clots that block blood flow to heart (heart attack) or brain (stroke)
constrict blood flow, increases blood pressure
how do blood clots in atherosclerosis occur
blood vessels lining smooth endothelial cells can rupture resulting in a rough surface. this exposes collagen and tissue factors, promoting activation of platelets and coagulation cascade
this forms thrombus (blood clot) formation - termed atherothrombosis
this blocks blood flow
thromboembolism
formed thrombus can break off from initial site and travel around the body
lodge elsewhere, blocks blood flow
can cause ischemia depending on where embolus gets stuck
ischemia
blood clot embolism leading to lack of blood reaching tissues
hypercholestrolemia
inc cholesterol in blood which can contribute to atheroma formation
HDL
high density lipoprotein
good cholesterol
absorbs cholesterol, carries back to liver
LDL
low density lipoproteins
bad cholesterol
contributes to atheroma
what is used to treat hypercholesterolemia
statins
statins are structurally related to ___ which is the substrate of ____
HMG-CoA
HMG-CoA reductase
statins have a ___ bioavailability as they have
low
extensive first pass metabolism and short half life
examples of prodrug statins
simvastatin
lovastatin
these are used to use first pass metabolism to our advantage - increases bioavailability
statins act on the same pathway as the nitrogen containing bisphosphonates used in ____
skeletal pharmacology
HMG-CoA is converted to ____ through HMG-CoA reductase
mevalonate
which can go on to produce cholesterol
statins interact with ___, inhibiting production of ___
HMG-CoA reductase
mevalonate
bisphosphonates are not front line therapies for hypercholesterolaemia. why
inhibits conversion of mevalonate via FDDP synthase
due to their impact on skeletal system
aspirin is also known as
acetylsalicylic acid
when is aspirin used
once atheroma has formed to prevent platelet aggregation
anti platelet therapy
also can use warfarin
standard dose of aspirin to prevent heart attack or stroke
75mg once a day
if previously patient has had stroke/ heart attack, this can be increased up to 300mg daily
standard dose of aspirin for pain relief
300 mg daily
metabolic pathway of aspirin
aspirin - inhibits platelet aggregation
undergoes phase 1 hydrolytic event, acetyl group removed forming salicylic acid
no platelet inhibition, but anti inflammatory
futher phase 2 metabolism to form glucoronide conjugate
inactive
why does the conversion from aspirin to salicylic acid cause anti inflammation
aspirin inhibits cyclooxygenase-1 (COX-1) which is constitutively expressed
this eventually inhibits formation of thromboxane A2/ platelet activation and aggregation
salicylic acid instead binds to COX-2, which is upregulated/ expressed only during inflammation, inhbiting production of pro-inflammatory prostaglandin
role of cyclooxygenase-1 COX-1
metabolise arachidonic acid into prostaglandin G2
which is then converted to prostaglandin H2
in platelets, can be then metabolised to thromboxane A2, which activates and aggregrates platelets
prostaglandin G2
short lived
salicylic acid has also been shown to inhibit COX-2 __ __
gene transcription
so reduces expression during inflammation, can be taken prophylactically
warfarin
anticoagulant
prevents clotting events like aspirin
but varies in therapeutic window between patients so difficult to dose correctly, also subject to changes in diet
warfarin mechanism of action
competitively inhibits vitamin k epoxide reductase complex 1 (VKORC1)
prevents reduction of oxidised vitamin k, thus cant be reused, vitamin k dependent carboxylase is inhibited, clotting is inhibited
vitamin k epoxide reductase complex 1 (VKORC1)
activates vitamin K for body - which allows for clotting events including healthy clotting events and preventing haemorrhage
reduces oxidised vitamin k to reduced vitamin k1, allowing it to be oxidised again to form clotting factors
vitamin k dependent carboxylase
converts hypofunctional factors into functional factors
aka into able to clot
dependent on oxidising vitamin k
clopidogrel
prodrug, targets platelet activation and aggregation
via inhibiting binding of ADP to P2Y12 receptor
__% of clopidogrel is converted into inactive metabolites by __
85
carboxylesterases
__% of clopidogrel undergoes first pass metabolism in the __ to active metabolite by conversion to __ , the active metabolite
15
2-oxo-clopidogrel
P2Y12
GPCR
expressed on platelets
purinergic
relevant in aggregration
P2Y12 is endogenously activated by __ causing
ADP
activation of COX-1, fibrinogen binding, clotting cascade
2-oxo-clopidogrel irreversibly binds to the
P2Y12 receptors
strong as contains thiol group which binds to free cysteine - high affinity
inhibits activation via ADP
how long does 2-oxo-clopidogrel effect last
platelets are effected for entire lifespan of approx 7-10 days as irreversible
only change when new P2Y12 formed via new platelets
angina
results from formation of atherosclerosis plaques in vessel walls, limits coronary blood flow and oxygen supply to myocardium
causes heavy weight feeling and pressure on chest
angina treatment
vasodilators
vasodilators example
glyceryl trinitrate or nitroglyceryin
glyceryl trinitrate or nitroglyceryin work on the same pathway as
sildenafil/ viagra
and amyl nitrites
nitric oxide
gaseous signalling molecule
vasodilators mechanism of action
nitric oxide crosses membrane effectively as gas
binds to guanylate cyclase
converts GTP to cGMP
reduces intracellular calcium ion stores
causes smooth muscle relaxation via myosin light chain phosphatase
increases blood flow
cGMP converted to GMP via phosphodiesterase
activation of phosphodiesterase shuts off cGMP, no more relaxation, cycles to GTP, cycle starts again
glyceryl trinitrate or nitroglyceryin is converted to nitric oxide, starts this system and leads to inc blood flow
glyceryl trinitrate or nitroglyceryin is converted to nitric oxide via
mitochondrial aldehyde dehydrogenase
how is glyceryl trinitrate or nitroglyceryin administered - 2
sublingual tablets or sprays under tongue to inc vascularisation and alleviate symptoms
reaches heart faster in angina attack
clinical issues we gaf ab - 6
cvd which include/ contributed to by
thromboembolism (which can cause ischemia)
hypercholestrolemia (can cause atheroma)
atheroma
blood clotting
atherosclerosis (can cause angina)
drugs used to treat
anticoagulant drugs - aspirin, warfarin, clopidogrel
lipid lowering drugs (for hypercholestrolemia)- prodrug statins (simvastatin, lovastatin)
angina treatments - nitroglycerin vasodilator
antihypertensive drugs - beta adrenoreceptor competitive antagonists (propanolol (atenolol, bisoprolol, metoprolol are cardioselective), calcium channel blockers
heart failure drugs - digoxin, amiodarone, candesartan, captopril
