drugs on blood vessels Flashcards
Why do we need appropriate blood pressure?
what is the issue with too low?
issue with too high? (3)
what is it important in treating?
Too low – systolic <60 mmHg, poor drive for end organ perfusion
Too high – damage blood vessels, and produces afterload which reduces cardiac output, increasing O2 demand of the heart which also alters end organ perfusion
Regulation of blood pressure and blood flow are important clinical objectives in treating cardiovascular disease, e.g. sepsis, hypertension
What effect does regulation of vascular tone have?
controls 2 things?
Regulation of vascular tone (controlling blood vessel radius) is central for controlling blood pressure and blood flow
What is vascular tone?
describes the degree of constriction of a blood vessel relative to maximum dilation
effect of increasing and decreasing vascular tone
Increasing vascular tone will increase blood vessel constriction and increase blood pressure
Reducing vascular tone will induce blood vessel dilation and reduce blood pressure
Effect sepsis has on the body
what does it cause excessive of? effect of this?
why is it a very complex condtion?
systemic infection, causes systemic excessive vasodilatation, decreases TPR, large drop in BP, no drive for end organ perfusion, end organ damage, very serious, ITU support
Very complex condition – potential involvement of all those endothelium-mediated vasodilation pathways
Effect of anaphylaxis has on the body
what type of reaction is it?
what does it cause and effect?
hypersensitivity reaction, systemic vasodilatation, poor end organ perfusion
Effect of heart failure on the body
3 main effects
Poor cardiac output, poor blood pressure and poor end organ perfusion
Vasoconstrictor mechanisms
receptors for NA /AD? Ang II? Vasopressin? ET-1? TXA2? what also activates these receptors? what is this response called?
what pathways does it activate and what does this produce?
what effect do these molecules have? (2 molecules with different effects)
Receptors NA / Ad : α1 Ang II : AT1 Vasopressin : V1 ET-1 : ETA TXA2 : TP Stretch also activates these receptors – Myogenic response
activates the Gq pathway so PiP2 becomes DAG and IP3 via PLC
DAG increase membrane permeability leading to depolarisation which leads to the Activation of voltage-gated Ca2+ channels (VGCCs) which induces Ca2+ influx
IP3 acts on the IP3 receptor on SR to release Ca2+ from stores which leads to contraction via the MLCK pathways
Using noradrenaline and adrenaline will drive these mechanisms to increase vasoconstriction
What are the different responses adrenaline have on resistance vessels?
most tissues?
muscle + heart?
Most tissues e.g Gi tract, skin -> vasoconstriction
skeletal muscle + coronary circulation -> vasodilation
What are the different responses noraadrenaline have on resistance vessels?
most tissues?
muscle + heart?
Most tissues e.g Gi tract, skin -> vasoconstriction
skeletal muscle + coronary circulation -> vasoconstriction
why are there different responses?
what receptor does adrenaline have higher affinity for?
what receptor does noradrenaline have higher affinity for?
what effect does a1 receptors have?
what effect does B2 receptors have?
what does skeletal muscle + heart tissues have more receptors of?
where does adrenaline mainly act and where does noradrenaline mainly act?
Adrenaline higher affinity for B over a adrenoceptors
Noradrenaline higher affinity for a over B adrenoceptors
a1 adrenoceptors produce contraction, B2 receptors produce relaxation
Skeletal muscle and coronary arteries have more B2 than a1 adrenoceptors
Giving adrenaline mainly acts at B2 to dilate vessels
Giving noradrenaline mainly acts at a1 receptors to constrict vessels
Effect of adrenaline on circulation
what will increase? what will it decrease? why?
effect on BP? why?
effect on CO? why?
will increase HR but tpr decreases due to vasodilation (B2 receptors) hence only small increase in BP
rise in hr will increase CO
Effect of noradrenaline on circulation
what happens to tpr and BP? why?
what happens to heart?
what happens to HR and why?
hence why give NA?
de increase in tpr due to vasoconstriction (a1 receptors) so BP will increase
As heart is B1 receprots, nto much effect by NA
baroreceptor stimulation - increase BP recognised by receptor leading to decrease in HR via vagus nerve
hence give NA – increase BP whilst protecting heart
Physiologically what does sympathetic nerve stimulaton do? (2 things)
noradrenaline (synapses) + adrenaline (adrenal gland) are both released
Pharamacological effects of NA
where does it primarily act? what 2 key effects does it have? effect on heart? clinical importance? important in which conditions?
NORAD is given to primarily act at a1-adrenoceptors on VSMCs
to increase TPR and increase blood pressure
Without having significant actions on heart (B1) – cardiac protective, doesn’t make the heart work hard to increase BP, blood flow
e.g. important in conditions such as sepsis, severe heart failure
Pharamacological effects of adrenaline
when is it given in high conditions?
importance of epipen
Adrenaline is given in high concentrations
to have an action on both B1 on the heart and a1 on VSMCs to raise BP
(also B2 in lungs to give bronchodilation)
e.g. epipen for anaphylaxis
when to give vasopressin in terms of situation
what does it act on and effect?
Can be given in sepsis
acts on v1 receptors for constriction
what causes rasied blood pressure (hypertension)?
what does this reduce? effect of this?
what is hypertension thought to be due to?
It is a cause of endothelium dysfunction
Reducing important tonic vasodilatation processes (e.g. NO, PGI2)
Causing poor end organ perfusion
Raised blood pressure is thought to be due to an imbalance of vasoconstrictor and vasodilator mechanisms
An excessive vascular tone in arterioles suppling end organs
Problems with hypertension
3 key issues
what does it mean for arterioles?
It increases afterload
Poor cardiac output
Heart has to work much harder
considerably raised blood pressure does not mean greater drive and greater blood flow
It means a greater pressure drop across arterioles
Higher pressure upstream, lower pressure (lower blood flow) downstream of excessive constriction
Vasoldilator mechanisms
how do they act?
what 3 key mechanisms are used for this? overall effect?
Block the vasoconstrictor receptors hence doesn’t activate pathway
open K+ channels which lead to hyperpolarisation and inactivate the VGCCS
Increase SERCA activity so More Ca2+ back into SR and increase Ca ATPase activity so there is more exclusion of Ca from the cell
Overall less Ca2+ in cell hence less MLCK and more MLCP therefore less contraction
Drug targets to prevent vasoconstriction
name the locations they can act
what molecules or can be done there
what is the effect of this
3 different locations
3 effects of nitrates
Block Gq receptors
(ARB, ACEi, α1 /ETA inhibitors)
Prevent vasoconstrictor pathway
Prevent increase in membrane excitability
(Nitrates, K channel openers)
Hyperpolarisation -> Inhibit VGCCs
Block VGCCs
(Dihydropyridines CCBs)
Less Ca2+ influx
Nitrates
Increase Exclusion of Ca2+ out of cell
Nitrates
Decrease Action of MLCK
Nitrates
Decrease Uptake into Ca2+ in SR
Effects of nitrates (4)
(Nitrates, K channel openers)
Hyperpolarisation -> Inhibit VGCCs
Nitrates
Increase Exclusion of Ca2+ out of cell
Nitrates
Decrease Action of MLCK
Nitrates
Decrease Uptake into Ca2+ in SR
Gq receptor blockers
4 antagonists where do they act example of the drugs effect of the drug when is it normally used
Angiotensin II receptor (AT1) antagonists (ARB) e.g. Losartan
Block AT1 receptors to reduce vasoconstriction – hypertension, heart failure
Angiotensin converting enzyme inhibitors (ACEi) e.g. Enalapril
Reduce Ang II levels – hypertension, heart failure
a1-adrenoceptor antagonists e.g. Prazosin
Competitive receptor antagonists – drug-resistance hypertension
ETA receptor antagonist e.g. Bosentan
Block ETA receptors which are upregulated in pulmonary artery hypertension
Ca influx blockers
2 different ways
example of drug
effect of the drugs
when is it normally used
VGCC blockers (CCB) e.g. Amlodipine Dihydropyridine subtype, vascular selective (not cardio), block influx of Ca2+ to reduce vasoconstriction – hypertension, angina
K Channel Openers e.g. Nicorandil
Hyperpolarisation, less VGCC activation/Ca influx, vasodilatation - angina
Contractile mechanism relaxants
2 relaxants
example of the drug
effect of the drug
when normally used
Nitrates e.g. Glyceryl trinitrate (GTN)
NO donors, PKG-mediated vasorelaxations – angina, pulmonary oedema
PDE5 inhibitors e.g. Sildenafil
Decrease cGMP breakdown, PKG-mediated vasodilatation – erectile dysfunction
