Drugs affecting the vasculature and blood pressure Flashcards
what is the role of endothelial cells?
provide a diffusion barrier but also inhibits platelet activation
more importantly - it can control the relaxation and contraction of smooth muscle cells
how do smooth muscle cells contract? the mechanisms is essentially the same as airway smooth muscle. Step 1-
calcium enters
how does calcium enter the SMC?
L-type channels or GPCR q11
what does calcium bind to once in the SMcell?
calmodulin
what does the Ca/calmodulin do?
converts MLCK into active MLCK
what does active MLCK do?
phosphorylates MLC causing contraction
which molecules is responsible for relaxation in SMC?
cGMP
what does cGMP do?
coverts MLC phosphatase into active form
what does active MLC phosphatase do?
dephosphorylaes MLC causing relaxation
which substances act on the endothelium to cause vasodilatation?
bradykinin
ADP
5HT
what do vasodilators on endotheliam dio?
allow GPCR to let in Ca into the cell ?
what does Ca in endothelial cells do?
binds to calmodulin
what does the Ca calmodulin complex do in endothlelial cells ?
activates nitric oxide synthase
what does nitric oxide synthase do?
converts L-arginine and oxygen to NO and citrulline
what does the NO producedby the endothelial cells then do?
diffuses into the SMC neighbouring it
what does NO in SMC do?
activates guanylate cyclase which converts GTP to cGMP
what does cGMP do?
causes relaxation through mechanism previously
what else can cGMP do?
activate protein kinase G activates Ca dependent K channels - causing K to leave and thus hyperpolarisation
what do organic nitrates do?
when metabolised they relesase NO into SMC and cause relaxation as above
in small doses what do organic nitrates do?
cause venorelaxation - decreases SV
what does small doses of organic nitrates do to the HR?
increase it so CO is maintained the same
what do organic nitrates do in larger doses?
cause arteriolar dilatation
what does arteriola dilatation cause?
decreases the arterial pressure so reduces afterload
- also decreases pulse wave reflection
why are organic nitrates useful in angina?
they cause decreased myocardial oxygen requirement via
1) decreased preload
2) decreased afterload
3) improved perfusion of the ischaemic zone
how do Organic nitrates cause improved perfusion to ischaemic zones?
they cause dilatation of collateral vessels
what are organic nitrates used in?
angina and acute coronary syndrome
what is the danger in unstable angina?
danger that a cap of atheromatous plaque is going to form a thrombus
what are the two examples of ONs?
GTN and Isosorbide mononitrate
what is GTn most effective in?
prevention rather than relief
what is the acting time?
short acting 30 mins
what is indicated if someone has a pain than goes away wtih GTN?
thye have angine and it is not an MI
what is ISM acting time and what is it used for?
prophylaxis of angina and acting is 4 hours
what are the side effects and problems of GTN and ISM?
- people can build up a tolerance
- postural hypotension
- headaches
how do the endothelium cause contraction in SMC?
they release endothelin which acts on ETa receptors in SMC
what kind of receptor is ETa?
GPCR- q11
what does the activation of this receptor cause ?
increase in Ca levels and thus contraction
how is the production of endothelin controlled?
either vasoconstrictor or dilators can influence the promotor region of the gene pre-proendothelin
what are some examples of vasoconstrictors?
adrenaline
angiotensin II
ADH (vasopressin)
what are some examples of vasodilators?
nitric oxide
natriuretic peptide (ABC)
shear stress
what does the RAAS system do?
increases bp and water retention
where is renin released from
granular cells in the kidneys
what causes renin to be released?
there is a decrease in the renal blood supply
which cells sense this decrease in renal blood supply?
manca cells
what could cause a decreased renal blood supply?
fall in renal BP or when there is a haemorrhage
what does renin do one in the circulation?
causes the conversion of angiotensinogen to angiotensin 1
what happens to angiotensin 1?
it is converted to angiotensin 2 by ACE
WHERE IS ACE LOCATED?
in the lungs
what does AG2 do?
activates the AT1 receptor which is a GPCR leading to
1) contraction of smooth muscle in vasuclature
2) cell growth in the heart and arteries
3) aldosterone secretion from the adrenal cortex
how is there contraction of vascular smooth muslce?
1) through activation of smooth muscle AT1 receptors
2) through increased release of noradrenaline from sympathetic nerves
what does the aldosterone secretion causE>
tubular reabsorption of Na and salt retention
overall what does the RAAS system do?
increases MABP and BLood volume
what is the role of ACE? it has 2 roles
1- Converts inactive angiotensin I to angiotensin II (vasoconstrictor)
2- Inactivates bradykinin (vasodilator)
give an example of an ace inhibitor?
lisinopril
what do ARBs do?
they are receptor antagonists of AT1 - so block the action of angiotensin 2
give an example of an ARB
losartan
what are the effects of ACE inhibitors ?
they cause venous dilatation (decreased preload) and arteriolar dilatation (decreased afterload and TPR)
what increases the effect of ACE inhibitors?
if the person is hypertensive or ont
also if the person is having diuretic therapy as there will be increased renin secretion
where do ACE inhibitors have the greatest effect?
in angiotensin sensitive vascular beds - like the brain, heart, kidney – important because this may help maintain perfusion of critical organs
what are some adverse effects of ACE inhibs
May initially cause hypotension – especially in patients treated with diuretics
Dry cough - this is because bradykinin is present in the airways and where it stimulates irritant receptors
why would an ARb be used instead of an ACE?
if the perosn has a cough
when are both ARBs and ACE inhibitors contraindicated>
in pregnancy (foetal toxicity) and should be not be used in bilateral renal artery stenosis (although ACEIs are used in diabetic nephropathy)
what are the clinical uses of ARB and ACE inhibitors? there are three
1- hypertension
2- cardiac failure
3 - following MI
what is the benefit of ARB and ACE in hypertension?
they
1) reduced TPR and MABP and
2) possible suppression of proliferation of smooth muscle cells in the media of resistance vessels
what is the benefit of ARB and ACE in HF and post MI ?
HF is associated with inappropriate activation of the RAAS. ACEIs 1) decrease vascular resistance improving perfusion; 2) increase excretion of Na+ and H20; 3) cause regression of left ventricular hypertrophy
what are adrenoceptors?
g-protein coupled receptors that are activated by the sympathetic transmitter noradrenaline and the hormone adrenaline
what are the different types of adrenoceptor?
a1,2
b1,2,3
what is the clinical use of beta adrenoceptor antagonists ?
- treatment of angina pectoris
- treatment of hypertension
- treatment of HF
what do B blockers do in angina? 3 things
1) decrease myocardial O2 requirement (decrease HR, SV, Work, O2)
2) counter elevated sympathetic activity associated with ischaemic pain
3) increase the amount of time spent in diastole (decrease HR) improving perfusion to the left ventricle
what do B blockers do in HT treatment ?
reduce CO
reduce renin release from the kidneys
a CNS action that reduces sympathetic activity
what do B blockers do in HF?
In combination with other drugs they suppress adverse effects associated with elevated activity of the sympathetic nervous system and RAAS
what do Ca antagonists do?
they prevent the opening of L-type channels in exciteable tissues in response to depolarisation and hence limit Ca entry
where are Ca channels found ?
in the heart and in smooth muscle
what do Ca antagonists do in AP of SA and AV nodes?
they modify upstroke and reduce the rate and conduction through the AV node
what do Ca antagonists do in AP of ventricular myocytes?
they act on phase 2 - reducing the force of contraction
what is the first step in calcium entry in vascular smooth muscle?
noradrenaline is released from sympathetic neurones to act on A1 adrenoceptors
what does the noradrenaline acting on a1 receptors cause? 2 things
leads to the release of Ca from intracellular stores (sarcoplasmic reticulum)
ALSO alpha 1 can activate Na receptors
what does the activation of Na receptors cause?
depolarisation via plasma membrane cation channels
what does depolarisation by Na channels cause?
the opening of ROCcs (calcium channels leading to an influx in Ca in plasma membrane l- type channels
what o Ca antagonists do?
they prevent the ROCC opening
give three examples of Ca antagonists
1) verapamil
2) amlopidine
3) diltiazam
what is verapamil relatively selective for?
cardiac L-type channels
what is amlopidine relatively selective for?
dihydropyridine compound - relitively selective for smooth muscle L-type channels
what are Ca antagonists used for clinically ?
1) hypertension - amlopidine
2) angina
3) arrhythmias
how do Ca antagonists work in Hypertension?
they reduce Ca entry into vascular smooth muscle cells causing generalized arteriolar dilatation, reducing TPR and MABP.
where the the major effect of Ca antagonists on smooth muscle?
on the arteries and arterioles with little effect on the veins
what are the adverse effects of Ca antagonists acting on smooth muscle?
hypotension, dizziness, flushing and ankle oedema
what are calcium blockers used for in angina?
as prophylactic treatment
what are ca antagonists often used in combination with if B blockers are contraindicated in the treatment of angina?
GTN
why are calcium blockers of use in angina? 2 things
1) they cause peripheral arteriolar dilatation decreasing afterload and myocardial oxygen requirement - preload is not significantly changed
2) they produce coronary vasodilatation
diltiazam and verapamil produce negative inotropic effects, what offsets this?
the activation of the baroreceptor reflex in response to vasodilatation and increased sympathetic activity
what do Ca antagonists treat in arrhythmias?
atrial fibrilation
how do Ca antagonists treat AF?
they reduced ventricular rate by suppression of conduction through the AV node
what should verapamil not be used in combination with?
B blockers
how do potassium channel openers cause relaxation?
they open ATP modulated K channels creating a hyperpolarisation effect as K leaves the cell. This switches off Ca L-type channels.
where are these ATP modulated K channels located?
in vascular smooth muscle - K openers act potently and primarily upon arterial smooth muscle
name a K opener that is used as a drug of last resort in severe hypertension ?
minoxidil
what are the adverse effects of minoxidil?
causes reflex tachycardia (prevented by a β-blocker) and salt and water retention (alleviated by a diuretic)
name a K opener that is used in Angina?
nicorandil
what do A1 receptor antagonists do?
Cause vasodilatation by blocking vascular α1-adrenoceptors. Reduced sympathetic transmission results in decreased MABP
give examples of a1 receptor antagonists ?
prazosin and doxazosin - both are competative antagonists
what are a1 blockers also used for?
also provide symptomatic relief in benign prostatic hyperplasia (an abnormally enlarged prostate that compresses the urethra) and are particularly indicated for hypertensive patients with this condition
give an adverse effect of A1 blockers
hypotension
what do diuretics do?
they act on the kidney to increase the excretion of Na, Cl and H20 and exert additional indirect , relaxant effects upon the vasculature
what are the two major classes of diuretics?
loop and thiazide
what do thiazide diuretics do?
inhibit NaCl reabsorption by the distal tubule by blocking te Na/Cl co-transporter
what percentage of filtered Na do they cause to be excreted alongside water?
up to 5% producing a moderate diuresis
what do loop diuretics do?
Inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle by blocking the Na+/K+/2Cl- co-transporter
what percentage of filtered Na do they cause to be excreted alongside water?
Cause up to 15-25% of
filtered Na+ to be excreted
with accompanying H20
producing a strong diuresis
what is undesirable about diuretics?
Thiazides and loop agents both produce an undesirable loss of K+
(that occurs through Na+/K+ exchange in the late distal tubule).
how is the loss of K corrected?
Corrected by co-administration of a ‘potassium sparring diuretic’
or K+ supplements
what are thiazides used in treatment for?
mild heart failure
hypertension
and also in severe resistant oedema (with a loop agent)
give an example of a thiazide diuretic?
bendroflumethiazide
what are loop diuretics used for?
Are used to reduce salt and water overload associated with:
- acute pulmonary oedema
- chronic heart failure
Benefit in these conditions occurs as a result of an absorption of extracellular fluid
contributing to oedema into capillaries as a consequence of diuretic-induced
reduction of blood volume
give an example of a loop diuretic
furosemide
