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Pharmacology and Therapeutics > 8. SNS agonists/antagonists > Flashcards

8. SNS agonists/antagonists Flashcards

1
Q

Where are sympathetic adrenoceptors found and how can they be activated (2 ways)?

A
  • Ends of sympathetic nerves

* Nervous (NA) and hormonal (adrenaline)

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2
Q

What do SNS agonists mimic the action of?

A

NA and adrenaline

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3
Q

What is the the predominant effect of sympathetic adrenoceptor stimulation in blood vessels?

A

Vasoconstriction due to α1 receptors

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4
Q

Which receptors are NA and adrenaline more selective for?

A
  • NA is slightly more alpha selective

* Adrenaline is slightly more beta selective

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5
Q

Where is NA derived from?

A
  • Tyrosine in the diet

* Tyrosine => DOPA => Dopamine => NA

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6
Q

Describe the α2 receptor

A
  • Pre-junctional receptor
  • Found on the neurone itself
  • NA released acts back on α2, diminishing sympathetic effects - negative feedback
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7
Q

Give examples of directly acting SNS agonists

A
  • Adrenaline (non-selective)
  • Phenylephrine (α1)
  • Clonidine (α2)
  • Dobutamine (β1)
  • Salbutamol (β2)
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8
Q

What happens in anaphylaxis?

A

• Sensitivity to innocuous (harmless) antigen

  • recognition by mast cells with IgG antibodies
  • mast cell degranulation
  • histamine release
  • bronchoconstriction + vasodilation
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9
Q

Why do we give adrenaline to treat anaphylaxis?

A
  • β2 - bronchodilation
  • β1 - tachycardia
  • α1 - vasoconstriction
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10
Q

Why can adrenaline be known as a physiological antagonist?

A

• Doesn’t actually bind to a receptor to produce a opposing effect (histamine receptor in this case)
• Ultimately produces a response to reverse effects of histamine
- reverses bronchoconstriction and increases HR and CO
- suppression of mediator release - adrenaline stops degranulation

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11
Q

What are the clinical uses of adrenaline (apart from anaphylaxis)?

A
  • β2 - asthma (emergencies - IM or subcutaneous), acute bronchospasm associated with COPD
  • β1 - cardiogenic shock - sudden inability of heart to pump sufficient blood
  • α1 - spinal anaethesia (maintain BP before surgery), local anaesthesia (vasoconstriction prolongs action of anaesthetic)
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12
Q

What are the unwanted effects of adrenaline?

A
  • Reduced and thickened mucous
  • Tachycardia, palpitations, arrhythmias
  • Cold extremities, hypertension
  • Overdose - cerebral haemorrhage, pulmonary oedema
  • Minimal GIT effects due to parasympathetic control
  • Tremor
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13
Q

What is phenylephrine?

A
  • Selective α1-adrenergic receptor agonist related to adrenaline
  • Very alpha selective (α1 > α2&raquo_space; β1/2)
  • More resistant to breakdown by COMT, but not MAO (compared to NA/A)
  • Very good nasal decongestant - α1-mediated vasoconstriction
  • Mydriatic - induces dilation of pupil for examination of the back of the eye
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14
Q

What is clonidine?

A

• Selective α2-adrenergic receptor agonist
• α2 > α1&raquo_space; β1/2
- negative feedback effect
- decreases sympathetic function
• Is a receptor agonist, even though it has an opposing effect

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15
Q

Why is clonidine used to treat glaucoma?

A

• Glaucoma - increased intraocular pressure
• Poor drainage of aqueous humour by the venous system
• Optic nerve can be permanently damaged - blindness
• Clonidine stimulates the α2-adrenoceptors on the ciliary body, reducing aqueous humour production
(• Stimulating α1-adrenoceptors can also help - vasoconstriction reduces blood supply to ciliary body, reducing AH production)

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16
Q

What can clonidine be used to treat (apart from glaucoma)?

A
  • Hypertension and migraine

* Reduces activation of heart, reduces renin production, reduces overall renin production

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17
Q

What is isoprenaline?

A
  • Beta selective (β1 = β2&raquo_space; α1 = α2)
  • Related to adrenaline
  • More resistant to MAO and uptake 1 - prolonged action
  • Used for cardiogenic shock, acute heart failure and MI
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18
Q

Why might β2-adrenoceptor stimulation be a problem?

A
  • Dilation of blood vessels in the muscles
  • Pooling of blood
  • Decreased venous return
  • Fall in venous bP
  • Stimulated baroreceptors
  • Reflex tachycardia triggered
  • Arrhythmias can be exacerbated - negatively impacts effective functioning of the heart
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19
Q

Why is dobutamine better than isoprenaline?

A
  • More β1 selective than isoprenaline
  • Less worry about reflex tachycardia arising

(however it has a half-life of 2 minutes as it’s rapidly metabolised by COMT)

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20
Q

What is salbutamol?

A
  • Synthetic catecholamine derivative with relative resistance to MAO and COMT
  • Much more β2 selective than other drugs - relaxation of bronchial smooth muscle
  • Decreased PI (type of lipids) hydrolysis
  • Increased Na/Ca exchange
  • Opens K+ channels
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21
Q

What are the clinical uses of salbutamol?

A

• Treatment of asthma (localised effect)
- relaxed bronchial smooth muscle
- inhibition of release of bronchoconstrictor substances from mast cells
• Treatment of threatened premature labour
- relaxation of uterine smooth muscle
- prevents abortion of a foetus

22
Q

What are the side-effects of salbutamol?

A
  • Reflex tachycardia
  • Tremor
  • Blood sugar dysregulation
23
Q

What does stimulation of β1-adrenoceptors result in, in the kidneys?

A

Renin release

24
Q

Describe the selectivity for carvedilol

A
  • Non-selective adrenoceptor antagonist (α1, β1, β2)

* α1 blockade gives additional vasodilator properties

25
Q

Describe the selectivity for phentolamine and propanolol

A
  • Phentolamine - α1 + α2 antagonist (non-selective for α)

* Propanolol - β1 + β2 antagonist (non-selective for β)

26
Q

Describe the selectivity for prazosin and atenolol

A
  • Prazosin - α1

* Atenolol - β1 (more so than β2)

27
Q

Describe the selectivity for nebivolol

A
  • Selective for β1

* Also potentiates NO

28
Q

Describe the selectivity for sotalol

A
  • β1 + β2

* Also inhibits K+ channels

29
Q

What are the main clinical uses of SNS antagonists

A

Same as SNS agonists (hypertension, arrhythmias, glaucoma etc.)

30
Q

Why are beta-blockers useful in treating hypertension, with reference to the adrenoceptors?

A
  • Heart (β1) to reduce HR and CO (effect disappears in chronic treatment)
  • Kidney (β1) to reduce renin production
  • β2 antagonism may be important - but what extent is not clear
  • β1 + β2 antagonism in CNS as this determines the BP set point - reduces sympathetic tone
31
Q

What is the significance of bronchoconstriction as a side effect of beta-blockers?

A
  • Little importance in the absence of airways disease
  • Can be dramatic and life-threatening in asthmatics
  • Also clinical importance in patients with COPD
32
Q

What is the effect of beta-blockers on hypoglycaemia?

A

• Masks the symptoms of hypoglycaemia (sweating, palpitations, tremor)
• Also block the β2-adrenoceptor-driven breakdown of glycogen => less glucose
- β1-selective agent have advantages

33
Q

Why can beta-blockers cause fatigue and cold extremities?

A
  • Fatigue - reduced CO and skeletal muscle perfusion due to β2-blockade on vasculature
  • Cold extremities - loss of β-adrenoceptor mediated vasodilation in cutaneous vessels
34
Q

What is the advantage of atenolol over propanolol?

A
  • Atenolol is β1-selective, rather than non-selective for β
  • Still antagonises the effects of NA on the heart
  • Less of an effect on airways (still not safe with asthmatics)
  • Less side effects

(selectivity is concentration dependent)

35
Q

What is the advantage of carvedilol over atenolol and propanolol?

A
  • Acts on α1 as well as β
  • α1 blockade - additional vasodilator properties
  • Still works more on β1 than α1
  • Lowers bP via reduction in TPR
  • Induces change in HR/CO like other drugs, but effect wanes with chronic use
  • Therefore, it’s a better anti-hypertensive drug, but has more side effects
36
Q

What type of receptors are α1 and α2?

A
  • α1 - Gq-linked (PLC => increased [intracellular Ca])

* α2 - Gi-linked (decreased cAMP => decreased NA release)

37
Q

What is phentolamine?

A
  • Non-selective α-blocker
  • Vasodilation (α1) - fall in BP
  • Increase in NA (α2 - reduced reuptake)
  • Used to treat pheochromocytoma-induced hypertension
  • Increased GIT motility - diarrhoea
38
Q

What are the negative CV effects of α-blockers?

A
  • Fall in TPR + BP => postural hypotension

* Reflex response - CO/HR increases - baroreceptor mediated tachycardia

39
Q

Why do α2 receptors and baroreceptors reduce the effectiveness of phentolamine?

A
  • Blockade of α2 => loss of negative feedback + increased NA
  • NA competes with phentolamine for α1
  • Baroreceptor reflex reduces effectiveness too
40
Q

Describe the effect of prazosin

A
  • α1-adrenoceptor antagonist
  • Vasodilation and fall in arterial pressure
  • CO decreases due to fall in venous pressure
  • Dramatic hypotensive effect (better than phentolamine as α2 feedback is still intact)
  • Doesn’t affect cardiac function appreciably
  • Also causes decreased LDL and increased HDL
41
Q

What is methyldopa and how does it work?

A
  • Anti-hypertensive drug
  • Taken up by noradrenergic neurones - decarboxylated and hydroxylated to form false transmitter - α-methyl noradrenaline
  • Not deaminated by MAO - accumulates >NA
  • Displaces NA from synaptic vesicles - released same way as NA
  • Less active than NA on α1 - less effective at vasoconstriction
  • More active on α2 - auto-inhibitory feedback stronger - reduces NA
  • CNS effects - stimulates vasopressor centre in brainstem to inhibit sympathetic flow
42
Q

Apart from it’s main use, what are the other effects of methyldopa, and what are the adverse effects?

A
  • Used in renal insufficiency or cerebrovascular disease
  • Recommended anti-hypertensive in pregnant women - no adverse on foetus despite crossing the blood-placenta barrier

• Dry mouth, sedation, orthostatic hypotension, male sexual dysfunction

43
Q

How do Class II Antiarrhythmics work?

A
  • Increase in sympathetic drive to the heart via β1 can precipitate or aggravate arrhythmias
  • Increase in sympathetic tone, particularly after MI
  • Beta-blockers increase the refractory period of the AV nodes
  • Interferes with AV conduction in atrial tachycardias and slows down ventricular rate
  • An unusual re-entry type electrical activity in damaged tissue won’t stimulate another heart beat
44
Q

What is angina?

A
  • Pain that occurs when oxygen supply to the myocardium is insufficient for its needs
  • Distributed across chest, arm and aneck
45
Q

What is stable angina?

A
  • Pain on exertion
  • Due to a fixed narrowing of the coronary vessels e.g. atheroma
  • Increased demand on the heart
46
Q

What is unstable angina?

A
  • Pain with less and less exertion, culminating with pain at rest
  • e.g. atheromatous plaque starting to rupture
  • Platelet-fibrin thrombus associated with the ruptured atheromatous plaque - but without complete occlusion
  • High risk of infarction
47
Q

What is variable angina?

A
  • Occurs at rest
  • Coronary artery spasm
  • Associated with atheromatous disease
48
Q

How do beta-blockers help with angina?

A
  • Decrease HR, SBP and cardiac contractile activity
  • β1-selective antagonists (metoprolol) can do this without affecting bronchial smooth muscle at low doses
  • Beta-blockers reduce oxygen demand (of heart) whilst maintaining same degree of effort
49
Q

What are the adverse effects of meoprolol (for angina)?

A
  • Fatigue
  • Insomnia
  • Dizziness
  • Sexual dysfunction
  • Bradycardia
  • Hypotension
  • Bronchospasm
50
Q

How do drugs that act on β-adrenoceptors treat glaucoma?

A
  • Aqueous humour is produced via carbonic anhydrase
  • Beta-blockers e.g. carteolol hydrochloride affects the action of carbonic anhydrase
  • Reduces the rate of AH production
51
Q

What can beta-blockers be used to treat other than hypertension, cardiac problems and glaucoma?

A
  • Anxiety - controls somatic symptoms associated with sympathetic over-reactivity e.g. palpitations and tremor
  • Migraine prophylaxis - maintains good blood supply within CNS
  • Benign essential tremor

Pharmacology and Therapeutics (33 decks)

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