SNS antagonists

Question 1

Adrenergic receptor subtype effects

Answer 1

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

Question 2

Where are a2 receptors found

Answer 2

ON the pre-synaptic sympathetic nerve membrane (not the postsynaptic membrane (the effector organ here)), they inhibit releaase of NE.

Question 3

Outline selectivity of 
Phentolamine
Prazosin
Propranolol
Atenolol

What can these drugs be used to treat

Answer 3

1. a1+a2
2. a1
3. b1 +b2
4. b1

Pindolol similar to atenolol!!!

adrenergic antagonists: 
HTN, 
arrythmias, 
angina, 
glaucoma,

Question 4

Goal of HTN threapy

Answer 4

reduce mortality from cardiovascular or renal events

Question 5

Which 3 main factors contribute to blood pressure

Answer 5

BP= CO*TPR

Blood volume
Cardiac output
Vascular tone

Question 6

Targets for antihypertensives

Answer 6

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.

Question 7

How do beta blockers work

Answer 7

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

Question 8

State the different beta blockers + their receptors

Answer 8

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)

Question 9

Side effects of beta blockers

Think BCDEF… H!

Answer 9

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

Question 10

Why have ACE inhibitors/ calcium channel blockers superseded b blockers

Answer 10

B blockers are no less effective BUT larger side effect profile

Question 11

Why atenolol vs propanolol in terms of receptor side effects

Answer 11

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

Question 12

Why does carvefilol have advanage over atenolol and propanolol

Answer 12

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

Question 13

How effective are following drugs:

atenolol, propanolol, carvedilol

Answer 13

carvedilol>atenolol>propanolol

Question 14

What g proteins are a1 and a2 linked to

Answer 14

a1 (the anomaly for g protein) –> Gq… ca2+ and dag etc

a2- Gi linked to decrease AC

Question 15

State a non-selective a blocker:

Answer 15

phentolamine

Question 16

What is phentolamine used for

Answer 16

• used to treat phaechromocytoma-induced hypertension

all the adrenaline being released would require some vasodilation

Question 17

State a a1 specific blocker

What is their use

Answer 17

prazosin inhibit the vasoconstrictor activity of NE

Alpha receptor blockers have modest blood pressure lowering effects (used as adjunctive treatment)

Question 18

Side effects of phentolamines

Answer 18

Increased GIT motility, diarrhea common problem

Question 19

How does the body reduce the effectiveness of phentolamine

Answer 19

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

Question 20

Why is prazosin better than phentolamine in terms of how the body reduces the effectiveness of these two drugs

Answer 20

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

Question 21

Mechanism of methydopa

Answer 21

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!!

Question 22

Clinical effects of methyldopa

Answer 22

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

Question 23

Side effects of methyldopa

Answer 23

dry mouth, sedation, Orthostatic hypotension, Male sexual dysfunction – rarely used

SODS (Sexual dysfunction in males, orthostatic hypotension, dry mouth and sedation)

Question 24

Define arrythmias

Answer 24

ABNORMAL OR IRREGULAR HEART BEATS…

not rhythmic contraction so you don’t get proper blood filling and CO falls

Question 25

Normal cause of arrythmia

Answer 25

Myocardial Ischemia.

Question 26

What class of arrythmia drugs are b blockers

Answer 26

Class II

Question 27

Why are beta blockers used in arrythmia

Answer 27

Sympathetic effects don’t cause arrythmias but can exacerbate them…
You block:

1. Increased sympathetic drive to heart. Precipitates arrhythmias
   b1
2. AV conductance dependent on sympathetic activity
   b1 (so useful in atrial tachycardia to slow ventricular rate)

Question 28

Differentiate stable and unstable angina and variable angina

Answer 28

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.

Question 29

How do beta blockers work in angina

Answer 29

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.

Question 30

Cause of glaucoma?

Answer 30

poor drainage of the aqueous humour. increasing intraocular pressure

Question 31

Why can b blockers be used in glauucome

Answer 31

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

Question 32

When can sotalol be used

Answer 32

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)

Question 33

T/f alpha blockers first line treatment for HTN

Answer 33

F: adjunctive

Question 34

Main b blocker for anti-arrythmias

Answer 34

propanolol