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Y2 LCRS 1 - Pharmacology and Therapeutics > SNS Antagonists > Flashcards

SNS Antagonists Flashcards

1
Q

Describe the effects of each type of adrenoceptor.

A

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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2
Q

Explain the adrenergic receptors present at a synapse.

A
  • 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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3
Q

State five adrenoceptor antagonists including the receptors that they block.

A
  • 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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4
Q

State four main clinical uses of adrenoceptor antagonists.

A
  • Hypertension
  • Angina
  • Arrhythmia
  • Glaucoma
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5
Q

Which equation is used to determine blood pressure.

A

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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6
Q

State three elements that contribute to hypertension.

A

Blood volume

Cardiac output

Vascular tone

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7
Q

What is defined as hypertension?

A

Having a BP consistently above 140/90 mmHg

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8
Q

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

A
  • 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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9
Q

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

A

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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10
Q

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

A

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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11
Q

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

A

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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12
Q

Name some different beta-blockers and state their selectivity.

A
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13
Q

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

A

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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14
Q

State some other unwanted effects of beta-blockers.

A

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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15
Q

What is the advantage of atenolol over propranolol?

A

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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16
Q

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

A

Selectivity is concentration dependent

  • Selectivity decreases as concentration increases
17
Q

What advantage does carvedilol have over atenolol and propranolol?

A
  • 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
18
Q

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

A

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
19
Q

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

A

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
20
Q

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

A
  • 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

21
Q

What are the effects of prazosin?

A

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
22
Q

Describe the mechanism of action of methyldopa.

A

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
23
Q

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

A

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
24
Q

What are some adverse effects of methyldopa?

A
  • 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
25
Q

Define arrythmia and what is its main cause.

A

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
26
Q

What can precipitate or aggravate arrythmias?

A

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
27
Q

What is atrioventricular (AV) conductance dependent on?

A

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
28
Q

How does propanolol help with treating arrythmia?

A

​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
      *
29
Q

What class of antiarrythmic drug is propanolol?

A

Class II

  • Antiarrythmic drugs are classified based on their mechanism of action
  • Class II = beta-blockers
30
Q

In what arrythmias is propanolol particularly successful?

A

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
31
Q

Define angina.

A

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
32
Q

Describe and explain the three different types of angina.

A

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
33
Q

Describe how beta-blockers can help prevent angina attacks.

A

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
34
Q

What is glaucoma characterised by?

A

Increase in intraocular pressure

35
Q

What is glaucoma caused by? What are the consequences?

A

Caused by poor drainage of the aqueous humour

If untreated, it permanently damages the optic nerve → blindness

36
Q

Where is aqueous humour produced?

A

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
37
Q

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

A

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
38
Q

Describe the flow and drainage of aqeous humour.

A

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
39
Q

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

A

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

Y2 LCRS 1 - Pharmacology and Therapeutics (38 decks)

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