SNS Antagonists Flashcards
What do alpha 1 receptors do?
- vasoconstriction
- relax GI tract
What do alpha 2 receptors do?
- inhibit neurotransmitter release
- contract vascular smooth muscle
- CNS effects
What do beta 1 receptors do?
- increased heart rate
- increased contractility
- relax GI tract smooth muscle
- renin release stimulated
What do beta 2 receptors do?
- bronchodilation
- vasodilation
- relax visceral smooth muscle
- hepatic glycogenolysis
What do beta 3 receptors do?
lipolysis
How does the presynaptic neurone monitor the neurotransmitter environment in the synapse?
They also bind to auto receptors on the pre-synaptic neurone (controls later synthesis and release)
What do pre-synaptic alpha 2 adrenoreceptors do?
They negatively affect NA synthesis and release (inhibitory)
What is carvedilol selective/nonselective for?
Non selective a1, b1, b2 antagonist
What causes the vasodilator properties of carvedilol?
the a1 antagonism
What is phentolamine selective/non selective for?
Non selective for alpha (1+2)
What is propranalol selective/non selective for?
Non selective for beta (1+2)
What is prazosin selective for?
alpha 1
What is atenolol selective for?
b1
What is nebivolol and sotalol selective?
N - b1
S - beta receptor selective and inhibits K+ channels
What are the clinical uses of SNS antagonism?
- hypertension
- cardiac arrhythmia
- angina
- glaucoma
What is the implication of hypertension on health?
Single most important risk factor for stroke, causing about 50% of ischaemic strokes (hypertension associated with atherosclerosis)
Accounts for ~25% of heart failure cases
Major risk factor for MI and CKD
How is blood pressure increased?
BLOOD VOLUME, CO AND VASCULAR TONE:
- increases renin
- increased HR and contractility
- venoconstriction
What are some targets for anti hypertensives?
- heart
- kidney
- arterioles
- sympathetic nerves
- CNS (determines BP set point)
Where do beta blockers act?
- CNS β to reduce sympathetic tone
- Heart (B1) β reduce ionotropic and chronotropic effect (this effect disappears in chronic treatment)
- Kidneys (B1) β reduce renin production (common long term feature is a reduction in TPR)
B1-receptor on the pre-synaptic membrane and blockade of this reduces positive feedback on NE release and may contribute to anti-hypertensive effects
What are the unwanted effects of beta blockers?
Bronchoconstriction β little importance unless the patient has an airway disease
Cardiac failure β in patients with heart disease this may be a problem
Hypoglycaemia - B blockers may mask symptoms (tremors etc.) and non-selective B -blockers will also block hepatic glycogenolysis (B2)
Fatigue β reduced CO
Cold extremities β loss of B-receptor mediated vasodilation
Bad dreams
What are the side effects of propranolol?
During exercise, can reduce HR, CO and ABP
As it is non-selective, it produces all the typical adverse effects
What are the side effects of atenolol?
- Antagonises the effects of NE on the heart but affects any organ with beta 1
- Less effect on airways than non-selective drugs but not safe with asthmatic patients
- Selectivity is concentration dependent( too much and it becomes non-selective)
What is labetalol?
A1 and B1 antagonist
- Lowers BP via reduction in TPR
- Induces a reduction in HR or CO but this effect wanes with chronic use
Why is atenolol better than propranalol?
Propranolol: Ξ²1 + Ξ²2 β Non-selective, βequalβ affinity for both Ξ²1 + Ξ²2 receptors.
Atenolol: Ξ²1 β more selective for beta 1 receptors.
Atenolol is beta 1 selective β cardio-selective drugs
It antagonises the effects of NA on the heart, but will affect any tissue with Ξ²1 receptors e.g. kidneys
It has less of an effect on airways than non-selective drugs, but still not safe with asthmatic patients
Propranolol also works on Ξ²2 receptors (in the airways and liver) -> even more side effects
Why is carvedilol better than propranalol and atenolol?
Carvedilol: Non-selective (a1+ Ξ²1 + Ξ²2) β alpha-1 blockade gives additional vasodilator properties.
Propranolol: Ξ²1 + Ξ²2 β Non-selective, βequalβ affinity for both Ξ²1 + Ξ²2 receptors.
Atenolol: Ξ²1 β more selective for beta 1 receptors.
- Carvedilol is a dual acting Ξ²1 and a1 antagonists so afffects vessels and TPR
- It works more on beta-1 receptors
- This drug lowers blood pressure by via a reduction in peripheral resistance
- Like Ξ²-blockers, carvedilol induces a change in HR or CO but this effect wanes with chronic use
- So carvedilol is the better anti-hypertensive drug, but it comes with more side effects
Describe what types of receptor and alpha 1 is and where it is found
Gq-linked (PLC -> increased [intracellular Ca]
- Postsynaptic on vascular smooth muscle
Describe what types of receptor and alpha 2 is and where it is found
- Gi-linked (decreased cAMP -> decreased NA release)
- Presynaptic autoreceptors inhibiting NE release
Give examples of alpha blockers
prazosin
phentolamine
What does prazosin act on and what is it used to treat?
Alpha 1 specific
Inhibit the vasoconstrictor activity of NE
Has modest blood pressure lowering effects
- adjunctive treatment
What does phentolamine act on and what is it used to treat?
Non-selective a-blocker Used to treat phaechromocytoma-induced hypertension (has GI side effects)
What are the side effects of an alpha antagonist?
The sympathetic drive is blocked and you get postural hypotension
β’ CO/HR increases β reflex response to fall in arterial pressure β this is baroreceptor mediated tachycardia
β’ Blood flow through cutaneous & splanchnic vascular beds increases
β’ But effects on vascular smooth muscle are slight
How does phentolamine work? What are some problems with it and SE?
Causes vasodilation and a fall in blood pressure due to blockade of alpha-1 adrenoceptors
However, blockade of presynaptic alpha-2 receptors removes the inhibitory effect of the alpha-2 receptors on noradrenaline release and so you get an increase in noradrenaline release. This enhances the reflex tachycardia that you get with any blood pressure lowering agent. Increased GIT motility -> diarrhoea
Why does alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?
- If you target alpha 1/2, you get a mixture of outcomes
- Blockade of alpha 2 receptors causes loss of negative feedback effects, which results in an increased release of NA. This NA competes with phentolamine for the alpha 1 receptor. Therefore, the effectiveness of phentolamine on alpha 1 blockage is reduced.
- When you reduce arterial pressure, baroreceptor firing rate decreases
- This leads to increased sympathetic and decreased parasympathetic activity coming from the medulla
- If the overriding effect is sympathetic, this has effects on the vasculature and the heart
How does prazosin work?
Why is it better than phentolamine?
SE?
- Vasodilatation and fall in arterial pressure
- Less tachycardia than non-selectives (no a2 actions)
- Cardiac output decreases, due to fall in venous pressure as a result of dilation of capacitance vessels
- Hypotensive effect is dramatic β better than phentolamine because a2 feedback is still in tact
- Postural hypotension
- Unlike other anti-hypertensives, a1-antagonists cause decreased LDL, and an increase in HDL cholesterol
What is methyldopa?
A false neurotransmitter - Taken up by noradrenergic neurons and enters the NA synthesis pathway
Describe the pathway that methyldopa takes
Decarboxylated and hydroxylated to form false transmitter, Ξ±-methyl-NA, which enters the synapse
How does methyldopa act on receptors?
- Has much less effect on adrenoceptors
- Alpha-methyl-NA is a pretty good alpha 2 agonist (not a great agonist for the other adrenoceptors)
β’ So in addition to poor stimulation of sympathetic adrenoreceptors, there is negative feedback via Ξ±2
β’ Therefore alpha-methyl-NA promotes sympathetic inhibition in 2 different ways
How does methyldopa interact with MAO and what is the effect of this?
- Not deaminated within neuron by Mono Amine Oxidase (MAO)
- Therefore tends to accumulate in larger quantities than NA
- It therefore displaces noradrenaline from the synaptic vesicles (competes to get uptaken and as more it is more competitive)
What are the effects of methyldopa?
- Alpha-methyl-NA promotes sympathetic inhibition
- Causes improved blood flow (less Ξ±1 stimulation -> less vasoconstriction)
- Anti-hypertensive, especially in the renal system (kidney disease) and CNS (cerebrovascular disease)
- Has some CNS effects, stimulates vasopressor center in the brain stem to inhibit sympathetic outflow
Cane methyldopa be given to pregnant women?
Yes, it has no adverse effects on the foetus despite crossing the blood-placenta barrier
What are the side effects of methyldopa?
Dry mouth, sedation, orthostatic hypotension (same as postural), and male sexual dysfunction β so rarely used.
What is an arrhthymia?
Abnormal of irregular hearbeats - main manifestation is myocardial ischaemia and can lead to an MI
How does the sympathetic nervous system affect arrhythmias?
Can contribute to arrhythmias/exacerbate arrhythmias
The sympathetic NS acts on nodal tissue in the heart to control pace maker current. It also acts in ventricular tissue to promote contraction.
The smooth transition of the current from the atria to the ventricles is incredibly important for effective CO. if the sympathetic NS increases, any underlying arrhythmias will be exacerbated.
What is AV conductance dependent on?
BETA 1 RECEPTORS
What do beta 1 antagonists do in terms of arrhythmias?
Increase the refractory period of the AV node. This interferes with AV conduction in atrial tachycardias, and to slow ventricular rate.
Give an example of a beta antagonist used for arrhythmias
Propranolol
- Reduce mortality of patients with myocardial infarction
- Particularly successful in arrhythmias that occur during exercise or mental stress
What is angina?
Angina is about pain β caused predominantly by poor blood flow through coronary vessels. It is strongly linked to atherosclerosis.
What are the 3 types of angina - describe them?
Stable β pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels e.g. atheroma.
Unstable β 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 β occurs at rest, caused by coronary artery spasm, associated with atheromatous disease.
Which drugs can be used for angina and why?
At low doses, Ξ²1-selective agents (metoprolol) reduce HR and contractile activity without affecting bronchial smooth muscle.
During exercise, coronary vessels dilate to deliver more oxygen to the heart to match increased demand. In angina, there is a mismatch. Beta-blockers decrease myocardial work; this reduces the oxygen demand whilst maintaining the same degree of effort.
This comes with a degree of exercise intolerance.
How can beta blockers be used to treat glaucoma?
- There are beta-1 receptors on the ciliary body β NA acts on these receptors linked to carbonic anhydrase
- Aqueous humour is produced by blood vessels in the ciliary body via the actions of carbonic anhydrase
- It flows into posterior chamber, through the pupil to anterior chamber, and then drains into trabecular network and into the veins and canal of Schlemm
- Production indirectly related to blood pressure and blood flow in ciliary body
- Beta-blockers reduce the effectiveness of carbonic anhydrase -> less aqueous humour produced
