Drugs affecting the vasculature and blood pressure Flashcards
1
Q
what is the role of endothelial cells?
A
provide a diffusion barrier but also inhibits platelet activation
more importantly - it can control the relaxation and contraction of smooth muscle cells
2
Q
how do smooth muscle cells contract? the mechanisms is essentially the same as airway smooth muscle. Step 1-
A
calcium enters
3
Q
how does calcium enter the SMC?
A
L-type channels or GPCR q11
4
Q
what does calcium bind to once in the SMcell?
A
calmodulin
5
Q
what does the Ca/calmodulin do?
A
converts MLCK into active MLCK
6
Q
what does active MLCK do?
A
phosphorylates MLC causing contraction
7
Q
which molecules is responsible for relaxation in SMC?
A
cGMP
8
Q
what does cGMP do?
A
coverts MLC phosphatase into active form
9
Q
what does active MLC phosphatase do?
A
dephosphorylaes MLC causing relaxation
10
Q
which substances act on the endothelium to cause vasodilatation?
A
bradykinin
ADP
5HT
11
Q
what do vasodilators on endotheliam dio?
A
allow GPCR to let in Ca into the cell ?
12
Q
what does Ca in endothelial cells do?
A
binds to calmodulin
13
Q
what does the Ca calmodulin complex do in endothlelial cells ?
A
activates nitric oxide synthase
14
Q
what does nitric oxide synthase do?
A
converts L-arginine and oxygen to NO and citrulline
15
Q
what does the NO producedby the endothelial cells then do?
A
diffuses into the SMC neighbouring it
16
Q
what does NO in SMC do?
A
activates guanylate cyclase which converts GTP to cGMP
17
Q
what does cGMP do?
A
causes relaxation through mechanism previously
18
Q
what else can cGMP do?
A
activate protein kinase G activates Ca dependent K channels - causing K to leave and thus hyperpolarisation
19
Q
what do organic nitrates do?
A
when metabolised they relesase NO into SMC and cause relaxation as above
20
Q
in small doses what do organic nitrates do?
A
cause venorelaxation - decreases SV
21
Q
what does small doses of organic nitrates do to the HR?
A
increase it so CO is maintained the same
22
Q
what do organic nitrates do in larger doses?
A
cause arteriolar dilatation
23
Q
what does arteriola dilatation cause?
A
decreases the arterial pressure so reduces afterload
- also decreases pulse wave reflection
24
Q
why are organic nitrates useful in angina?
A
they cause decreased myocardial oxygen requirement via
1) decreased preload
2) decreased afterload
3) improved perfusion of the ischaemic zone
25
how do Organic nitrates cause improved perfusion to ischaemic zones?
they cause dilatation of collateral vessels
26
what are organic nitrates used in?
angina and acute coronary syndrome
27
what is the danger in unstable angina?
danger that a cap of atheromatous plaque is going to form a thrombus
28
what are the two examples of ONs?
GTN and Isosorbide mononitrate
29
what is GTn most effective in?
prevention rather than relief
30
what is the acting time?
short acting 30 mins
31
what is indicated if someone has a pain than goes away wtih GTN?
thye have angine and it is not an MI
32
what is ISM acting time and what is it used for?
prophylaxis of angina and acting is 4 hours
33
what are the side effects and problems of GTN and ISM?
- people can build up a tolerance
- postural hypotension
- headaches
34
how do the endothelium cause contraction in SMC?
they release endothelin which acts on ETa receptors in SMC
35
what kind of receptor is ETa?
GPCR- q11
36
what does the activation of this receptor cause ?
increase in Ca levels and thus contraction
37
how is the production of endothelin controlled?
either vasoconstrictor or dilators can influence the promotor region of the gene pre-proendothelin
38
what are some examples of vasoconstrictors?
adrenaline
angiotensin II
ADH (vasopressin)
39
what are some examples of vasodilators?
nitric oxide
natriuretic peptide (ABC)
shear stress
40
what does the RAAS system do?
increases bp and water retention
41
where is renin released from
granular cells in the kidneys
42
what causes renin to be released?
there is a decrease in the renal blood supply
43
which cells sense this decrease in renal blood supply?
manca cells
44
what could cause a decreased renal blood supply?
fall in renal BP or when there is a haemorrhage
45
what does renin do one in the circulation?
causes the conversion of angiotensinogen to angiotensin 1
46
what happens to angiotensin 1?
it is converted to angiotensin 2 by ACE
47
WHERE IS ACE LOCATED?
in the lungs
48
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
49
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
50
what does the aldosterone secretion causE>
tubular reabsorption of Na and salt retention
51
overall what does the RAAS system do?
increases MABP and BLood volume
52
what is the role of ACE? it has 2 roles
1- Converts inactive angiotensin I to angiotensin II (vasoconstrictor)
2- Inactivates bradykinin (vasodilator)
53
give an example of an ace inhibitor?
lisinopril
54
what do ARBs do?
they are receptor antagonists of AT1 - so block the action of angiotensin 2
55
give an example of an ARB
losartan
56
what are the effects of ACE inhibitors ?
they cause venous dilatation (decreased preload) and arteriolar dilatation (decreased afterload and TPR)
57
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
58
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
59
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
60
why would an ARb be used instead of an ACE?
if the perosn has a cough
61
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)
62
what are the clinical uses of ARB and ACE inhibitors? there are three
1- hypertension
2- cardiac failure
3 - following MI
63
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
64
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
65
what are adrenoceptors?
g-protein coupled receptors that are activated by the sympathetic transmitter noradrenaline and the hormone adrenaline
66
what are the different types of adrenoceptor?
a1,2
| b1,2,3
67
what is the clinical use of beta adrenoceptor antagonists ?
- treatment of angina pectoris
- treatment of hypertension
- treatment of HF
68
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
69
what do B blockers do in HT treatment ?
reduce CO
reduce renin release from the kidneys
a CNS action that reduces sympathetic activity
70
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
71
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
72
where are Ca channels found ?
in the heart and in smooth muscle
73
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
74
what do Ca antagonists do in AP of ventricular myocytes?
they act on phase 2 - reducing the force of contraction
75
what is the first step in calcium entry in vascular smooth muscle?
noradrenaline is released from sympathetic neurones to act on A1 adrenoceptors
76
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
77
what does the activation of Na receptors cause?
depolarisation via plasma membrane cation channels
78
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
79
what o Ca antagonists do?
they prevent the ROCC opening
80
give three examples of Ca antagonists
1) verapamil
2) amlopidine
3) diltiazam
81
what is verapamil relatively selective for?
cardiac L-type channels
82
what is amlopidine relatively selective for?
dihydropyridine compound - relitively selective for smooth muscle L-type channels
83
what are Ca antagonists used for clinically ?
1) hypertension - amlopidine
2) angina
3) arrhythmias
84
how do Ca antagonists work in Hypertension?
they reduce Ca entry into vascular smooth muscle cells causing generalized arteriolar dilatation, reducing TPR and MABP.
85
where the the major effect of Ca antagonists on smooth muscle?
on the arteries and arterioles with little effect on the veins
86
what are the adverse effects of Ca antagonists acting on smooth muscle?
hypotension, dizziness, flushing and ankle oedema
87
what are calcium blockers used for in angina?
as prophylactic treatment
88
what are ca antagonists often used in combination with if B blockers are contraindicated in the treatment of angina?
GTN
89
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
90
diltiazam and verapamil produce negative inotropic effects, what offsets this?
the activation of the baroreceptor reflex in response to vasodilatation and increased sympathetic activity
91
what do Ca antagonists treat in arrhythmias?
atrial fibrilation
92
how do Ca antagonists treat AF?
they reduced ventricular rate by suppression of conduction through the AV node
93
what should verapamil not be used in combination with?
B blockers
94
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.
95
where are these ATP modulated K channels located?
in vascular smooth muscle - K openers act potently and primarily upon arterial smooth muscle
96
name a K opener that is used as a drug of last resort in severe hypertension ?
minoxidil
97
what are the adverse effects of minoxidil?
causes reflex tachycardia (prevented by a β-blocker) and salt and water retention (alleviated by a diuretic)
98
name a K opener that is used in Angina?
nicorandil
99
what do A1 receptor antagonists do?
Cause vasodilatation by blocking vascular α1-adrenoceptors. Reduced sympathetic transmission results in decreased MABP
100
give examples of a1 receptor antagonists ?
prazosin and doxazosin - both are competative antagonists
101
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
102
give an adverse effect of A1 blockers
hypotension
103
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
104
what are the two major classes of diuretics?
loop and thiazide
105
what do thiazide diuretics do?
inhibit NaCl reabsorption by the distal tubule by blocking te Na/Cl co-transporter
106
what percentage of filtered Na do they cause to be excreted alongside water?
up to 5% producing a moderate diuresis
107
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
```
108
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
109
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).
110
how is the loss of K corrected?
Corrected by co-administration of a ‘potassium sparring diuretic’
or K+ supplements
111
what are thiazides used in treatment for?
mild heart failure
hypertension
and also in severe resistant oedema (with a loop agent)
112
give an example of a thiazide diuretic?
bendroflumethiazide
113
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
114
give an example of a loop diuretic
furosemide
