SNS Antagonists Flashcards by Nazifa Ahsan

Describe the effects of each type of adrenoceptor.

α1:

Vasoconstriction
Relaxation of GIT

α2:

Inhibition of neurotransmitter release
Contraction of vascular smooth muscle
CNS actions

β1:

Increased cardiac rate and force
Relaxation of GIT
Renin release from kidney.

β2:

Brochodilation
Vasodilation
Relaxation of visceral smooth muscle
Hepatic glycogenolysis

β3:

Lipolysis

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Explain the adrenergic receptors present at a synapse.

NA released into synaptic cleft
NA binds to adrenergic receptor on effector (e.g. α1 on vascular smooth muscle cells)
The presynaptic neurone also contains autoreceptors
- They also bind to NA
- Their function is to monitor the NT environment within the synapse
- This influences release of further NTs
When NA binds to presynaptic α2 receptors, it inhibits further release of NA from the presynaptic nerve terminal by negative feedback

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State five adrenoceptor antagonists including the receptors that they block.

Carvedilol - non-selective (α1+ β1)
- Non-selective refers to the fact that they are non-selective to just alpha or beta
- Block both adrenergic receptor types
Phentolamine - α1+ α2
Prazosin - α1
Propranolol - β1 + β2
Atenolol - β1

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State four main clinical uses of adrenoceptor antagonists.

Hypertension
Angina
Arrhythmia
Glaucoma

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Which equation is used to determine blood pressure.

Blood Pressure (BP) = Cardiac Output (CO) x Total Peripheral Resistance (TPR)

NOTE: When we refer to blood pressure we are referring to the arterial pressure

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State three elements that contribute to hypertension.

Blood volume

Cardiac output

Vascular tone

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What is defined as hypertension?

Having a BP consistently above 140/90 mmHg

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Why is hypertenson so dangerous and what is the main goal of treating it?

Single most important risk factor for stroke, causing about 50% of ischaemic strokes
Accounts for approx. 25% of heart failure (HF) cases, this increases to approx. 70% in the elderly
Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)

Ultimate goal of hypertension therapy is to reduce mortality from cardiovascular or renal events

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What are the tissue targets for anti-hypertensive drugs? State the receptors of each tissue that beta blockers would target.

Sympathetic nerves:

The ones to BVs release the vasoconstrictor noradrenaline

Kidneys:

Regulates blood volume and vasoconstriction (via RAAS)

Heart:

Determines CO

Arterioles:

Determine peripheral resistance (TPR)

CNS:

Determines blood pressure set point
Regulates some systems involved in BP control & ANS

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State the receptors of each tissue that beta blockers would target.

Anti-hypertensive actions of beta blockers primarily mediated by blockade of β1 receptors

Kidneys - β1:

Reduced renin production

Heart - β1:

Reduced CO
This effect disappears in chronic treatment (probably some kind of tolerance mechanism)

Arterioles - not targeted:

Vasoconstriction is α1 mediated, so generally cannot be targeted by beta blockers
Generally, you don’t want to target the α1 receptors and cause vasodilation as a first-line of treatment due to side-effects (e.g. reflex tachycardia)

Sympathetic nerves - β1/β2:

There are some beta receptors on sympathetic nerves - less knowledge out there on this

CNS - β1/β2:

Some beta receptors in brain tied to CNS control of blood pressure - less knowledge out there on this
Reduction in sympathetic tone

Arterioles - not targeted:

You don’t want to target the α1 receptors and cause just vasodilation as a first-line of treatment due to side-effects (e.g. reflex tachycardia)

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Describe the mechanism of action of beta blockers in treating hypertension.

Through β1 blockade:

↓ in HR & FOC (SV) - ↓ in CO
- Reduction in CO means reduction in BP
- Thsi also means that the heart does not have to work as hard
↓ renin - ↓ angiotensin II (Ang II) release
- Ang II - potent vasoconstrictor & increases aldosterone production (leads to increase in blood volume)
*Blockade of the facilitatory effects of presynaptic β-adrenoceptors on noradrenaline release may also contribute to the antihypertensive effect
Essentially means presynaptic β-adrenoceptors facilitates/stimulates NA release

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Name some different beta-blockers and state their selectivity.

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State four conditions in which you would not give a patient a betablocker. Explain each of them.

Asthma – blockade of beta 2 receptors in the lungs can take away the beta 2 mediated bronchodilation, which can be fatal in asthmatics Cardiac Failure – these patients rely on a certain degree of sympathetic drive to the heart to maintain adequate cardiac output COPD – same reason as asthma Diabetes – beta blockade masks the symptoms of hypoglycaemia (e.g. tremors, palpitations, sweating) and beta 2 blockade also inhibits hepatic glycogenolysis

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State some other unwanted effects of beta-blockers.

Bronchoconstriction

Bronchodilation is mediated by the SNS via β2- receptors
- Blockage → bronchoconstriction
This isn’t important in the absence of airway disease
BUT could be dangerous is someone with asthma (life-threatening) or obstructive lung disease such as COPD
- Airway already obstructed, so don’t want to cause further bronchoconstriction and obstruction

Cardiac failure

Patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output
Removal of this by blocking β−receptors will produce a degree of cardiac failure (i.e. insufficient CO)

Hypoglycaemia

Glucose release from the liver is controlled by β2- receptors
- Glycogenolysis and gluconeogenesis → HGO
- Blockage → reduced HGO and hypoglycaemia
The use of β-antagonists could also mask the symptoms of hypoglycemia (sweating, palpitations, tremor)
- These symptoms are sympathetic effects - SNS stimulated during hypoglycaemia
- Beta blockers blocking SNS in general

Fatigue

Due to reduced cardiac output and reduced muscle perfusion
- Loss of β2 mediated vasodilation to increase blood flow to skeletal muscle during times of increased need/usage (e.g. exercise)

Cold Extremities (i.e. hands and feet)

Loss of β2-receptor mediated vasodilation in cutaneous vessels
- Function of this in ‘fight or flight’ is to keep you cool overall - heat radiating away from blood into environment
- Vasoconstriction → reduced blood supply → reduced warmth (as blood has a role in heat transfer to tissues)

Bad dreams

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What is the advantage of atenolol over propranolol?

Propanolol:

Non-selective beta blocker
‘Equal’ affinity for β1 & β2 receptors
Therefore could cause β2 mediated unwanted effects

Atenolol:

β1-selective beta blocker - i.e. cardioselective
More selective for β1 receptors
Therefore β2 mediated unwanted effects less likely
BUT although it has less effect on airways than non-selective drugs, but still not safe with asthmatic patients

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Why would you still not give a β1-selective beta blocker to an asthmatic patient?

Selectivity is concentration dependent

Selectivity decreases as concentration increases

What advantage does carvedilol have over atenolol and propranolol?

Carvedilol is a dual acting β1 and α1 antagonists
- Higher ratio of β1 to α1 (4:1).
Like β-blockers, carvedilol, induces a change in heart rate or cardiac output (but this effect decreases with chronic use)
However, due to the α1 blockade, this drug also lowers blood pressure via a reduction in peripheral resistance
- Blocks α1 mediated vasoconstriction

What types of receptors are α1 and α2 adrenoceptors and where are they found.

All adrenoceptors are G-protein coupled receptors

α1-receptors:

Gq-linked
Postsynaptic on vascular smooth muscle

α2-receptors:

Gi-linked
Presynaptic autoreceptors inhibiting NA release

Give some examples of different types of alpha blockers and when they are used.

Phentolamine:

Non-selective α-blocker
Used to treat phaechromocytoma-induced hypertension
- Phaechromocytoma = catecholamine secreting tumour of adrenal medulla
- Too much adrenaline and NA

Prazosin:

α1 specific blocker
Inhibits the vasoconstrictor activity of NA
Has modest blood pressure lowering effects
- Not as powerful antihypertensive as phentolamine
- Not very clear why this is
Only used as adjunctive treatment
- Used to assist a primary treatment of hypertenion

State some of the problems with non-selective alpha blockers (e.g. phentolamine).

You would get a fall in arterial pressure
- Alpha 1-adrenoceptors main mediators of peripheral resistance
- Vasodilation → reduced TPR → reduced BP
This would lead to postural hypotension
- The main response to prevent postural hypotension is peripheral vasoconstriction ( TPR) which increases MAP
- This is due to blood pooling in the distensible/compliant veins when you have been sitting down

Cardiac output/heart rate increases -

Baroreceptor mediated reflex tachycardia
This reflex response to fall in arterial pressure (mediated by the beta-adrenoceptors)
This is due to blockade of the alpha 2 receptors which would increase NA release

Other side effects:

Increased GI motility → diarrhoea
- This makes sense because you are blocking alpha receptors
- Alpha receptors are involved in reduction of GI motility and tone
Blood flow through cutaneous & splanchnic vascular beds increased
- Alpha receptors are involved in sphinter contraction to reduce blood flow to GI tract
- Cutaneous vasoconstriction mediated by alpha 1 receptors
But effects on vascular smooth muscle are slight - i.e. these effects are slight

Phentolamine no longer in clinical use

What are the effects of prazosin?

Prazosin is highly selective for alpha 1 receptors.

This leads to vasodilation and fall in arterial pressure

This should in theory be more effective than phentolamine (not understood why not) because:

Less tachycardia than non-selective antagonists since they do not increase noradrenaline release from nerve terminals - i.e. no alpha 2 actions actions
Cardiac output decreases, due to fall in venous pressure as a result of dilation of capacitance vessels
- Reduced EDV → reduced preload → reduced force of contraction (SV) → reduced CO

Describe the mechanism of action of methyldopa.

Methyldopa is an antihypertensive agent

Methyldopa is taken up by the noradrenergic neurons
It is decarboxylates and hydroxylated to form the false transmitter: alpha-methyl noradrenaline
It is NOT deaminated (i.e. broken down) within the neuron by MAO so tends to accumulate in larger quantities than noradrenaline in the pre-synaptic terminal
- MAO breaks down NA inside the pre-synaptic termina into metabolites
It displaces noradrenaline from the synaptic vesicles
- There is more of the false transmitter so it is more likely to be packaged into vesicles than NA
- Hence it is displacing NA
The false transmitter (alpha-methyl noradrenaline) is released in the same way as noradrenaline
- So more false transmitter and less NA is released
It is less active than noradrenaline on alpha-1 receptors
- i.e. less efficacy
This means that it is LESS EFFECTIVE AT CAUSING VASOCONSTRICTION
- Reduced TPR → reduced BP
Also, it is more powerful on presynaptic alpha-2 receptors
This means that the auto-inhibitory feedback mechanism operates more strongly and reduces noradrenaline release below normal levels
- This means that even less NA is being released so even less NA to compete with the false transmitter for the alpha 1 receptors
- So this allows an even greater proportion of the alpha 1 receptors to be occupied by the false transmitter rather than NA

State some other benefits of methyldopa other than its effect as an anti-hypertensive.

By bieng less effecive at vasoconstriction and thereby reduces TPR → improved blood flow

Other treatment uses:

Renal - kidney disease
- Improving blood flow to kidneys increases the amount of blood getting filtered
- This helps reduce build-up of toxic substances or waste products in the blood
CNS - cerebrovascular disease
- Problem with blood vessels affects blood supply to brain
  - Most commonly ischaemia due to narrowing of arteries (atherosclerosis) or a blood clot
- So vasodilation and widening of the BVs could help counteract this problem and improve blood supply

What are some adverse effects of methyldopa?

Dry mouth
- Reduced alpha-adrenoceptor stimulation inhibits salivary secretion
Sedation
- NA involved in control of arousal in the brain so lack of NA effect/activity results in sedation
Orthostatic hypotension
- reduced TPR
Male sexual dysfunction
- Alpha and beta adrenergic pathway involved in regulating erectile function
- So disruption causes dysfunction

Define arrythmia and what is its main cause.

Arrythmia = abnormal or irregular heartbeats Main cause: myocardial ischaemia NOTES: * Arrythmia has caused 350, 000 Deaths in US alone * Sinus arrhythmia = a normal variation of sinus rhythm, where the heart rate increases very slightly as you take a breath in. * Sinus rhythm, sinus bradycardia, sinus tachycardia and sinus arrhythmia are all normal heart rhythms where the electrical impulses travel in a normal way through the heart * *So these don't count as arrythmia - only inappropriate sinus tachycardia does*

What can precipitate or aggravate arrythmias?

An increase in sympathetic drive to the heart via beta-1 receptors * *Many types of arrythmia are due to fast heart rhythms* * *e.g. Atrial fibrillation = rapid and irregular beating of atria* * *Therefore, increase in SNS and hence HR would exacerbate the symptoms or stimulate (precipitate) the tachycardia*

What is atrioventricular (AV) conductance dependent on?

Rate of AV conductance dependent on **sympathetic drive** * Mediated by the **beta 1** receptor * The refractory period of the AV node is increased by beta-adrenoceptor antagonists * This interferes with AV conduction in atrial tachycardias, and acts to slow ventricular rate * *This allows more time for the ventricles to fill before contracting and emptying to allow a sufficient CO*

How does propanolol help with treating arrythmia?

Propanolol: * Non-selective beta-antagonist * Effects mainly attributed to beta 1 antagonism * Reduces mortality of patients with myocardial infarction * *Beta antagonists lower HR and contractility → reduced CO and hence BP* * *This means the metabolic demand of the heart is lowered as it isn’t having to work as hard* * *With MI, because some cells have already died, the other cells are having to work harder anyway* * *If they are made to work too hard and their metabolic demands are not met, this could lead to their death, rendering the heart an insufficient pump which causes DEATH* *

What class of antiarrythmic drug is propanolol?

**Class II** * Antiarrythmic drugs are classified based on their mechanism of action * Class II = beta-blockers

In what arrythmias is propanolol particularly successful?

Particularly successful in arrhythmias that **occur during exercise or mental stress** * *Exercise/mental stress involves increased HR (tachycardia)* * *By controlling HR you can control/prevent the tachycardia and its associated types of arrythmia*

Define angina.

Pain that occurs when the oxygen supply to the myocardium is insufficient for its needs * Chest pain * May also radiate to arm and neck *(typically left side)* * Pain distribution due to _referred pain_

Describe and explain the three different types of angina.

**Stable** * pain on exertion (and excitement) * This is when there is an increased demand on the heart * Due to fixed narrowing of the coronary vessels e.g. atheroma. **Unstable** * Pain with less and less exertion, culminating with pain at rest * *Essentially the pain doesn't just come with exertion like stable angina but it starts to come during times of less and less exertion, even at rest* * Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but **without complete occlusion** of the vessel * *This means that the blockages (reduction in blood supply) have reached a critical level* * Risk of infarction *(tissue death due to ischaemia)* **Variable** * Occurs at rest * Caused by coronary artery spasm * *Spasm = involuntary muscular contraction – sudden and temporary* * Associated with atheromatous disease * *Atherosclerosis is linked to changes in endothelial cells,* *so maybe they become more sensitive to vasoconstrictors, leading to the spasms*

Describe how beta-blockers can help prevent angina attacks.

At low doses, beta 1-selective agents *(e.g. metoprolol)*: * Reduce heart rate and myocardial contractile activity * BUT do **not** affect bronchial smooth muscle * *i.e. do not cause bronchoconstriction* * Therefore, they reduce the oxygen demand whilst maintaining the same degree of effort * *This means that you are less likely of getting to a situation where the oxygen supply to the myocardium is insufficient for its needs - i.e. angina*

What is glaucoma characterised by?

Increase in intraocular pressure

What is glaucoma caused by? What are the consequences?

Caused by poor drainage of the aqueous humour If untreated, it permanently damages the optic nerve → blindness

Where is aqueous humour produced?

They are produced by blood vessels in the **ciliary body** via the actions of **carbonic anhydrase** * *Carbonic anhydrase catalyses formation of carbonic acid from carbon dioxide and water* * *This carbonic acid dissociates into H+ and bicarbonate* * *Bicarbonate essential for active secretion of ions into the aqueous humour* * *Water follows due to osmosis* * *More water → more fluid → more aqueous humour*

What is the amount of aqueous humour produced related to to?

Indirectly related to **blood pressure** and **blood flow** in the ciliary body * *More blood flow → more ultrafiltration of plasma → more aqueous humour formation* * *In the ciliary processes, the hydrostatic pressure difference between capillary pressure and intraocular favors fluid movement into the eye* * *Higher hyrostatic pressure → more fluid pushed out into eye* NOTE: Aqueous humour formation involves: * Active secretion * Ultrafiltration * Simple diffusion

Describe the flow and drainage of aqeous humour.

Flows into posterior chamber, through the pupil to anterior chamber Drains into: trabecular network → canal of Schlemm → veins NOTE: * Anterior chamber = between cornea and iris * Posterior chamber = between iris and lens

Describe how adrenoceptor antagonists could be used in the treatment of glaucoma.

Beta blockers: * Beta 1 receptor on ciliary body (epithelial cells) coupled to carbonic anhydrase * Blocking beta 1 receptor reduces carbonic anhydrase action * This in turn reduces aqueous humour production