SNS antagonists Flashcards
Adrenergic receptor subtype effects
a1- vasoconstriction, relaxation of GIT
a2- inhibition of transmitter release, conraction of VSM, CNS action (also inhibitory)
b1- increased HR and force, renin release kidney, relaxation of gut
b2- bronchodilation, vasodilation (skeletal muscle), relaxation of siceral smooth muscle, hepatic hylogenolysis
b3- lipolysis
Where are a2 receptors found
ON the pre-synaptic sympathetic nerve membrane (not the postsynaptic membrane (the effector organ here)), they inhibit releaase of NE.
Outline selectivity of Phentolamine Prazosin Propranolol Atenolol
What can these drugs be used to treat
- a1+a2
- a1
- b1 +b2
- b1
Pindolol similar to atenolol!!!
adrenergic antagonists: HTN, arrythmias, angina, glaucoma,
Goal of HTN threapy
reduce mortality from cardiovascular or renal events
Which 3 main factors contribute to blood pressure
BP= CO*TPR
Blood volume
Cardiac output
Vascular tone
Targets for antihypertensives
The heart – cardiac output
Sympathetic nerves that release the
vasoconstrictor noradrenaline.
The Kidney - blood volume/vasoconstriction
Arterioles-determine peripheral resistance.
CNS-determines ‘blood pressure set point’ and regulates some systems involved in Blood pressure control & autonomic NS.
How do beta blockers work
Block increase HR and contractility, (b1)
Decreases renin release and thus blood volume (b1)
Sympathetic nerves release vasoconstrictor noradrenaline (b1/b2 receptors act opposite to a2 in terms of increaseing NE release, so we block this effect)
Blocks b1/2 receptors which control BP in CNS
State the different beta blockers + their receptors
Propanalol (b1+b2), atenolol (b1), carvedilol (b1 and b2 +a1),
other (nebivolol =b1 antagonist AND NO release), sotalol (non selective beta blockade and inhibits k+ channels –> look at electrical effects on the heart)
Side effects of beta blockers
Think BCDEF… H!
Bronchoconstriction- only in asthma/COPD (even in b1 selective, can still block b2 in lungs so these shouldn’t be given to asthmatics)
Cardiac failure- need some symp. drive to heart (note that EXCESS SNS is damaging to HF but you still need some sympathetic drive)
Bad dreams
Cold extremeties- Loss of b-receptor mediated vasodilatation in cutaneous vessels
Fatigue- decrease cardiac output and muscle perfusion (because b2 blocked so can’t have vasodilation of skeletal muscle)
Hypoglycaemia- inhibit glycogen breakdown (not good for diabetics)… also sympathetic effects (i.e. tremor, palipitations etc.) which tell diabetics that they are hypo are blocked by these drugs so they don’t know
Why have ACE inhibitors/ calcium channel blockers superseded b blockers
B blockers are no less effective BUT larger side effect profile
Why atenolol vs propanolol in terms of receptor side effects
You get less bad side effects from blocking b2 (these are effects of BLOCKING b2 not the normal effects of b2):
- less bronchoconstriction
- less hypoglycaemia
- less poor perfusion of muscle (so less fatigue)
atenolol is ‘cardioselective’ i.e. b1 selective so you avoid the side effects associated with b2
Why does carvefilol have advanage over atenolol and propanolol
You also block vasoconstriction, and all the heart/kidney mediated effects, but still don’t get b2 effects
Dual acting b1 and a1 antagonists, higher ratio of b1 to a1 (4:1).
This drug lowers blood pressure by via a reduction in peripheral resistance.
Like b-blockers, carvedilol, induces a change in heart rate or cardiac output but this effect wanes
How effective are following drugs:
atenolol, propanolol, carvedilol
carvedilol>atenolol>propanolol
What g proteins are a1 and a2 linked to
a1 (the anomaly for g protein) –> Gq… ca2+ and dag etc
a2- Gi linked to decrease AC
State a non-selective a blocker:
phentolamine
What is phentolamine used for
- used to treat phaechromocytoma-induced hypertension
all the adrenaline being released would require some vasodilation
State a a1 specific blocker
What is their use
prazosin inhibit the vasoconstrictor activity of NE
Alpha receptor blockers have modest blood pressure lowering effects (used as adjunctive treatment)
Side effects of phentolamines
Increased GIT motility, diarrhea common problem
How does the body reduce the effectiveness of phentolamine
You block the alpha 1 receptor which reduces vasoconstriction and thus blood pressure
But you also block a2 receptor, so you LOSE the -ve feedback effect because the inhibitory a2 are blocked on sympathetic nerve so you increase the NE in the synapse.
More NE in the synapse then you get competition between phentolamine and NE in the synapse!
Also, baroreceptors detect lower pressure (reduced baroreceptor firing rate), and this then causes physiological response of increasing CO (reflex tachycardia), which is not blocked because there is no beta blockade
Why is prazosin better than phentolamine in terms of how the body reduces the effectiveness of these two drugs
You don’t get alpha 2 blockade with prazosin (as it is alpha 1 selective), therefore you don’t get less inhibition of NE and the [NE] in synapse does not increase
BUT you still get the reduced baroreceptor firing rate and thus rebound tachycardia
Mechanism of methydopa
1 & 2 – Methyldopa converted to false
transmitter (alpha methylnoradernaline)
3 – Less active at Beta1/beta 2/Alpha 1 receptor
4 – Not metabolised well by MAO
5 – More likely to accumulate and displace
Noradrenaline in the NT containing vesicles, so it compettively ihibits the noradrenalin
So you get less beta and alpha 1 effects
But it’s a very good agonist at a2 receptor, so you enhance the negative feedback and you get less NE release too!!
Clinical effects of methyldopa
Major effect is improved blood flow (less vasoconstriction), due to enhancement of a2 mediated inhibition from the pre-synaptic membrane of the post-ganglionic neurone and also blockade of a1-mediated vasoconstrictive…..
Anti-hypertensive, and especially used when you want to improve blood flow!
Renal – kidney disease
CNS – cerebrovascular disease
Side effects of methyldopa
dry mouth, sedation, Orthostatic hypotension, Male sexual dysfunction – rarely used
SODS (Sexual dysfunction in males, orthostatic hypotension, dry mouth and sedation)
Define arrythmias
ABNORMAL OR IRREGULAR HEART BEATS…
not rhythmic contraction so you don’t get proper blood filling and CO falls
Normal cause of arrythmia
Myocardial Ischemia.
What class of arrythmia drugs are b blockers
Class II
Why are beta blockers used in arrythmia
Sympathetic effects don’t cause arrythmias but can exacerbate them…
You block:
- Increased sympathetic drive to heart. Precipitates arrhythmias
b1 - AV conductance dependent on sympathetic activity
b1 (so useful in atrial tachycardia to slow ventricular rate)
Differentiate stable and unstable angina and variable angina
Stable-pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels e.g. atheroma.
Unstable-pain with less and less exertion, culminating with pain at rest. Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel. Risk of infarction.
Variable-occurs at rest, caused by coronary artery spasm, associated with atheromatous disease.
How do beta blockers work in angina
You reduce the work of the heart by reducing HR, preload, contractility etc.
At low doses, b1-selective agents, metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle.
Cause of glaucoma?
poor drainage of the aqueous humour. increasing intraocular pressure
Why can b blockers be used in glauucome
B1 receptor couple to carbonic anhydrase, which makes HCO3 which is component of aqeous humour….
If you blocks b1 then it means less HCO3 and less aqeuous humour
When can sotalol be used
They are non selective beta blocker and inhibit K+ channels, can be used to slow heart down and the blockade of Ikr channels slows heart in cardiac arrythmias (i.e so mixed class II and class III in the Vaughn Williams classification)
T/f alpha blockers first line treatment for HTN
F: adjunctive
Main b blocker for anti-arrythmias
propanolol
