Introduction to the PNS: Adrenergic therapeutics

Question 1

1) which amino acid is noradrenaline synthesised from?

2) where is noradrenaline released from?

Answer 1

1) tyrosine via dopamine which is a precursor
2) released by post-ganglionic sympathetic nerves
- (noradrenaline -> adrenaline: hormone secreted by adrenal gland)

Question 2

all postganglionic sympathetic fibres release noradrenaline. which receptors does noradrenaline act on?

Answer 2

act either on α or β-adrenoceptors

Question 3

list the different Adrenoceptor subtypes and their locations

Answer 3

1) α1: smooth muscle
2) α2:smooth muscle
3) β1: heart
- increase cardiac rate and force
4) β2:smooth muscle heart
- Vasodilation, Bronchodilation
5) β3: skeletal muscle,fat

Question 4

for each of the Adrenoceptor subtypes state the G-protein they are coupled to and the response

Answer 4

1) α1: Gαq - Increase in IP3
2) α2:Gαi/o- decrease in cAMP
3) β1-3: Gαs: increase in cAMP

Question 5

outline the cardiovascular effects of Noradrenaline, Isoprenaline and Adrenaline

Answer 5

1) Noradrenaline:α-selective: causes vasoconstriction (α1), this causes reflex bradycardia (baroreceptor response) due to ACh action at vagal nerve. Overall increase in arterial (blood) pressure
2) Isoprenaline:β-selective: causes vasodilation (β2); tachycardia (β1). Overall decrease in BP
3) Adrenaline: β > α : intermediate action, low concentration ~ ISO; higher conc. ~ NA

Question 6

outline the difference between a cholinergic and a Adrenergic synapse

Answer 6

1) Adrenergic- no acetylcholinesterase instead there is a uptake 1’ transport system which can remove adrenaline
2) Tyrosine hydroxylase only found in noradrenergic neurones

Question 7

how is noradrenaline regulated in Adrenergic transmission?

Answer 7

1) noradrenaline regulates its own release by feeding back on α2 receptors ( negative feedback loop)
2) the body regulates noradrenaline by using the uptake 1 and uptake 2 system

Question 8

outline the therapeutic uses of adrenoceptor agonists on the following:

1) cardiovascular
2) respiratory
3) Urinary

Answer 8

1) Cardiovascular:
- Cardiac arrest: adrenaline IV
- Cardiogenic shock: β1-selective adrenoceptor agonist dobutamine acts to increase cardiac output
2) Respiratory: Asthma: β2-selective agonists salbutamol, terbutaline (short-acting) are inhalation bronchodilators; salmeterol, formoterol (long-lasting) used for chronic, nocturnal but not acute, attacks.
3) Urinary: Overactive bladder (incontinence): β3-selective agonist mirabegron

Question 9

outline the therapeutic uses of adrenoceptor agonists on the following:

1) Anaphylaxis
2) Local anaesthesia

Answer 9

1) Anaphylaxis: Adrenaline (EpiPen®) is life-saving in acute hypersensitivity; acts to cause bronchodilation (via β2 adrenorecptor) and to raise blood pressure (via α1 adrenoceptor)
2) Local anaesthesia: Adrenaline is used to prolong LA action e.g. lidocaine in dental procedures, bupivacaine in spinal anaesthesia

Question 10

What are the effects of histamine release as a result of Anaphylaxis on the body?

Answer 10

1) bronchoconstriction
2) vasodilation
3) inflammation

Question 11

outline the therapeutic uses of adrenoceptor agonists on the following:

1) Glaucoma
2) LabouR

Answer 11

1) Glaucoma: Adrenaline or brimonidine, apraclonidine (both selective α2-agonists) can be used to reduce intra-ocular pressure in patients
2) Labour: β2-selective agonists ritodrine or salbutamol act as a smooth muscle relaxant to inhibit sympathetic-induced contraction of the pregnant uterus to prevent premature labour at 24 - 33 weeks gestation

Question 12

Outline the therapeutics uses of α-adrenoceptor antagonists on the following:

1) Hypertension
2) Benign prostatic hyperplasia

Answer 12

1) Hypertension: Doxazosin or terazosin act on α1 adrenoceptors to cause vasodilation and decrease arterial blood pressure
2) Benign prostatic hyperplasia: α1A-adrenoceptor selective antagonists alfuzosin, indoramin or tamsulosin relaxes smooth muscle in bladder and prostate to treat enlargement and urinary retention.

Question 13

Outline the therapeutic uses of β-adrenoceptor antagonists on the following:

1) Cardiovascular
2) Glaucoma
3) migraine

(important)

Answer 13

1) Cardiovascular: The β-blockers propranolol, timolol (non-selective), metoprolol, atenolol (β1-selective) and acebutolol, pindolol (partial agonists) are important drugs in the treatment of angina, myocardial infarct, dysrhythmia, heart failure and hypertension
2) Glaucoma: Topical β-blocker commonly the drug of first choice: betaxolol , carteolol or timolol eye drops used; act to reduce production of aqueous humor and thus reduce intraocular pressure
3) Migraine: Propranolol or metaprolol use in migraine prophylaxis

Question 14

summarise the Side-effects of β-adrenoceptor antagonists

Answer 14

1) Even ‘cardioselective’ β-blockers contraindicated in patients with asthma or obstructive airways disease (e.g. bronchitis, emphysema)
2) Dangerous cardiac depression/bradycardia
3) Eye drops used for glaucoma are contraindicated in patients with cardiovascular disease.
4) β2 receptors control glucose release from liver; contraindicated in patients prone to hypoglycaemia
5) Fatigue: β-blockers can cause tiredness
6) Cold extremities (due to reduced blood flow)

Question 15

Why are there so many side-effects with cholinergic and adrenergic drugs?

Answer 15

The autonomic and somatic nervous systems are fundamental to human life (for homeostasis); any therapeutic intervention will thus have important effects

Question 16

what are the therapeutic uses of partial adrenoceptor agonists?

Answer 16

1) Clonidine is an α2 partial agonist used in hypertension. Presynaptic action reduces NA release (and thus α1-mediated vasoconstriction).
2) can down-regulate α2 adrenoceptors leading to hypertensive crisis if withdrawn too quickly

Question 17

outline the therapeutic uses of Indirect sympathomimetics

Answer 17

1) Topical ephedrine or systemic pseudoephedrine (Sudafed®) used as nasal decongestants. Act as substrates for uptake/transport system leading to NA release
2) Tyramine, amphetamine (and derivatives) used therapeutically in nacrolepsy, appetite suppression and ADHD
3) Blockers of uptake 1 are psychoactive agents: Cocaine, tricyclic antidepressants (imipramine) used to treat depression (potentiates biogenic amines including NA and serotonin

Question 18

Which two enzymes break down Catecholamines?

Answer 18

1) Monoamine oxidase (MAO) MAO-A and MAO-B isoforms.
- Found in mitochondria in sympathetic nerve terminals, liver and intestinal epithelium.
2) Catechol-O-methyl-transferase (COMT)

Question 19

outline the therapeutic uses of MAO inhibitors (MAOI)

Answer 19

1) Phenelzine is an antidepressant (used if SSRIs/TCA are ineffective)
2) Selegiline, rasagiline used in Parkinsons Disease (MAO-B selective): prevent dopamine breakdown to slow PD progression

Question 20

summarise where therapeutically important drugs act on in adrenergic transmission

Answer 20

1) Adrenoceptors (α and b)
- Agonists (cardiac arrest: α1; asthma: β2)
- Antagonists (cardiovascular: β; hypertension: α1)
- Partial agonists (hypertension: β, α2)
2) Transporters (uptake 1)
- Sympathomimetics: decongestants (ephedrine), amphetamine
- Blockers: antidepressants (TCA)
3) Metabolism
- Enzyme inhibitors: antidepressants (MAOI)
- False transmitter: hypertension (α-methylDOPA)

Question 21

A small boy is admitted to A&E with hot, dry skin and mouth, he is red, excited and delirious. On questioning, he was playing in woodlands and is known to have eaten something. What are the principles of treatments?

Answer 21

Anticholinesterase- increase cholinergic transmission

Question 22

Mrs W. is a long-term hospital patient who suffers muscle weakness, associated fatigue and drooping eyelids is being treated with a similar drug to that used above. What auto-immune disease is Mrs W. suffering from?

Answer 22

Myasthenia gravis

Question 23

A farm worker is admitted to A&E, he is sweating and complains of abdominal pain. He is agitated red and has difficulty breathing. His pupils are constricted and he has a pulse rate of 45. What are the principles of treatments?

Answer 23

Atropine – block muscarinic transmission

Question 24

Mr X is been prescribed timolol. He begins to complain of breathing difficult. What may be missing from his diagnosis? Which drug should he be given?

Answer 24

Airway problems (eg asthma, emphysema) timolol is non-selective, 
a selective β2 antagonist is needed eg. atenolol, metaprolol

Question 25

A young girl who was playing in her garden is admitted to A&E with swollen lips, eyelid and tongue and with severe breathing difficulty. What is the immediate treatment? What is the therapeutic basis of the treatment?

Answer 25

IM adrenaline, to reverse inflammatory mediator effects in anaphylaxis

Question 26

Mr Y is being treated for depression, he attends a party and starts to feel dizzy and nauseous. On checking, his blood pressure is dangerously high. What is the likely cause of his BP rise?

Answer 26

Taking MAOI and sufferingadverse reaction to foods high in tyramine