Pharmacology of the ANS

Question 1

What are the 3 methods of neurotransmitter elimination from the synaptic cleft?

Answer 1

• Re-uptake
• Diffusion
• Breakdown

Question 2

Why is neurotransmitter elimination from the synaptic cleft important?

Answer 2

It prevents receptor desensitisation in the post-synaptic membrane.

Question 3

Which post-synaptic receptors are faster: ionotropic receptors or metabotropic receptors?

Answer 3

Ionotrophic Receptors

Question 4

What type of post-synaptic receptors are GPCRs?

Answer 4

Metabotrophic Receptors

Question 5

Give 2 examples of drugs that target voltage-gated Na+ to inhibit the signal.

Answer 5

Lignocaine (local anaesthetic)
Phenytoin (used to treat epilepsy, which is over-excitation)

Question 6

Give an example of a drug that targets voltage-gated Ca2+ to inhibit the transmitter release.

Answer 6

Ziconotide (experiemental drug to treat neuropathic pain).

Question 7

Give an example of a drug that targets inhibition of exocytosis.

Answer 7

Botulinum toxin A – ‘Botox’:
Blocks exocytosis of acetylcholine. Involved in balancing muscle tone in cerebral palsy, treatment of hypersecretory disorders.

Question 8

Give an example of a drug that targets presynaptic transmitter uptake.

Answer 8

Fluoxetine - blocks pre-synaptic uptake of serotonin.

Question 9

Which named drug do I need to know that effects Parasympathetic Activation of ACh M2 muscarinic Receptors in the Heart?
How does it work?

Answer 9

**Atropine **is a non-selective muscarinic antagonist (can antagonist at ALL muscarinic receptors) used in treatment of bradycardia.
M2 Receptors are Gi coupled - inhibit adenylyl cyclase, active K+ channels, hyperpolarising the membrane of muscle cells, reducing rate of contraction.
Would be administered i.v.

Question 10

Which named drugs do I need to know that effect Sympathetic Activation of NA β1-muscarinic Receptors in the Heart?

Answer 10

• Adrenaline
• Isoprenaline
• Dobutamine
• Propanolol
• Atenolol

Question 11

How can adenaline be used as an agonist at NA β-muscarinic Receptors in the Heart?

Answer 11

• Used in treatment of cardiac arrest (i.v. - unless circulation has stopped, then intracardially (directly into the heart)).
• Only selective for adrenoreceptors (any sub-type).

Question 12

How can isoprenaline be used as an agonist at NA β-muscarinic Receptors in the Heart?

Answer 12

• Treatment of shock (now rarely used).
• It is a non-selective β adrenoreceptor agonist (will work on all β adrenoreceptors).

Question 13

How can dobutamine be used as an agonist at NA β-muscarinic Receptors in the Heart?

Answer 13

• Selective for β1 receptors
• Use to treat cardiac arrest, cardiogenic shock, cardiac surgery.

Question 14

How can propanolol be used as an antagonist at NA β-muscarinic Receptors in the Heart?

Answer 14

• Treatment of angina, arrhythmia, recovery from myocardial infarction, hypertension. Effect depends on prevalent sympathetic tone: very little at rest. With exercise, decrease of cardiac output.
• Side effects: bradycardia, cold extremities, risk of bronchoconstriction.
• Non-selective β-antagonists.

Question 15

How can atenolol be used as an antagonist at NA β-muscarinic Receptors in the Heart?

Answer 15

• Treatment of cardiovascular disease, and symptoms of anxiety (peripheral and central effect).
• Specific to β1 receptors.

Question 16

What type of GPCRs are sympathetic NA β1receptors in the heart?

Answer 16

• Gs coupled
• Increase cAMP signalling.

Question 17

What type of GPCRs are sympathetic NA α1Receptors in Vascular Smooth Muscle? What types of smooth muscle are they found in?

Answer 17

• Gq-coupled, increase Ca2+ (contraction).
• Skin, GI tract and kidney vascular smooth muscle

Question 18

What type of GPCRs are sympathetic NA β2 receptors in Vascular Smooth Muscle? What types of smooth muscle are they found in?

Answer 18

• Gs increasing cAMP, relaxation.
• Heart, brain, lungs and skeletal muscle vascular smooth muscle

Question 19

Which named drug do I need to know that effects Parasympathetic Activation of ACh M3 Muscarinic Receptors in Vascular Endothelial Cells?
How does it work?

Answer 19

Glycerol Trinitrate:
- A nitric oxide donor, lowers blood pressure to treat rapid onset angina.
- ACh M3 Muscarinic Receptors are Gq-coupled, increase intracellular Ca2+.
- Stimulates nitric oxide (very membrane-permeable signalling molecule) production in endothelial cells.
- Indirectly relaxes vascular smooth muscle.

Question 20

Which named drugs do I need to know that effect Sympathetic Activation of Noradrenaline / Adrenaline α1 and β2 Receptors in Vascular Smooth Muscle?

Answer 20

• Adrenaline (agonist)
• Phenylephrine (agonist)
• Phentolamine (antagonist)
• Prazosin (antagonist)

Question 21

How can adenaline be used as an agonist at NA α1 and β2 Receptors in Vascular Smooth Muscle?

Answer 21

• To treat anaphylaxis (i.m.) and to prolong actions of local anaesthetics via local vasoconstriction.
• It is a non-selective agonist, slightly less α-selective than NA.

Question 22

How can phenylephrine be used as an agonist at NA α1 and β2 Receptors in Vascular Smooth Muscle?

Answer 22

• Treatment of acute hypotension.
• Over The Counter nasal decongestant.
• Systemic side effects: hypertension - and reflex bradycardia.
• An α1 –selective agonist.

Question 23

How can phentolamine be used as an antagonist at NA α1 and β2 Receptors in Vascular Smooth Muscle?

Answer 23

• Control of hypertension in phaeochromocytoma (adrenal tumour - the tumour may be caused uncontrolled release of adrenaline).
• Reversible competitive α-antagonist.

Question 24

How can prazosin be used as an antagonist at NA α1 and β2 Receptors in Vascular Smooth Muscle?

Answer 24

• Antihypertensive.
• Side effects: postural hypotension, headache, reflex tachycardia.
• α-antagonist

Question 25

Which named drug do I need to know that effects parasympathetic Activation of ACh M3 Muscarinic Receptors in the Airways? How does it work?

Answer 25

**Ipratropium**: Agonist drug that can be inhaled to treat asthma through muscle relaxation. - ACh M3 Muscarinic Receptors are Gq coupled - activating PKC and subsequent increase in intracellular Ca2+

Question 26

Which named drugs do I need to know that effect Sympathetic Activation of Noradrenaline β2 Receptors in Smooth Muscle of Trachea and Bronchi?

Answer 26

- Salbutamol (β2 –selective agonist: β2 > β1): Anti-asthmatic by inhalation, short acting. Also used as tocolytics, i.e. to inhibit premature labour. - Salmeterol (β2 –selective agonist: β2 > β1): Anti-asthmatic by inhalation, longer term action. - Receptors are Gs-coupled (increasing cAMP, relaxation).

Question 27

How does a parasympathomimetic drug work?

Answer 27

Agonist drug that activates PNS receptors.

Question 28

How does a sympatholytic drug work?

Answer 28

Antagonist drug that blocks sympathetic action relative to parasympathetic action.

Question 29

Which parasympathetic receptors are activated in digestion? What effect does this produce?

Answer 29

- **ACh** activates **M3 muscarinic receptors (Gq-coupled)** in **gastro-intestinal smooth muscle**. - Contraction, increasing peristalsis, food is moved along GI tract. - **ACh** activates **M1** and **M3 muscarinic receptors** in **GI tract glands:** - Stimulates secretion of saliva and stomach acid.

Question 30

Which drugs are agonists / antagonists at ACh M3 and M1 receptors in PNS involved in digestion?

Answer 30

- **Pilocarpine**: Parasympathomimetic agonist drug that activates M3 receptors -> increase in saliva production. - **Bethanechol**: Parasympathomimetic agonist drug that activates M3 receptors -> increase of peristalsis in GI tract. - **Atropine, hyoscine**: Non-selective antagonists at muscarinic receptors: Used to reduce secretions (e.g. preparing patient for surgery). - **Pirenzepine**: M1 antagonist used to reduce acid secretion in stomach (formerly used in treatment for peptic ulcers).

Question 31

Which sympathetic receptors are activated in digestion and metabolism? What effect does this produce?

Answer 31

- **NA** activates α and β receptors in **liver** and **adipose** tissue: - Glycogenolysis. - Gluconeogenesis. - Lipolysis (fat mobilisation). - **NA** activates β2 receptors in the GI tract: - Relaxation of smooth muscle: decreased peristalsis.

Question 32

What is a drug that affects sympathetic activation of receptors involved in digestion and metabolism? How does it work?

Answer 32

**Clenbuterol**: sympathomimetic agonist doping agent (banned in competitive sports): activates β2 adrenoreceptors increasing muscle mass and speed of contraction in skeletal muscles, increasing lipolysis in adipose tissue, increased bronchodilation.

Question 33

Which receptors are involved in parasympathetic activation of the bladder? How do they work?

Answer 33

- **ACh** activates **M3 muscarinic receptors (Gq-coupled)** in the **bladder detrusor muscle.** - Smooth muscles contract promoting bladder emptying.

Question 34

Which drugs are agonists / antagonists at ACh M3 receptors in PNS in the bladder?

Answer 34

- **Bethanechol**: parasympathomimetic agonist drug activating M3 receptors, assisting bladder emptying. - **Darifenacin**: parasympatholytic M3 antagonist, used in treatment of urinary frequency, urgency and incontinence.

Question 35

Which receptors are involved in sympathetic activation of the bladder? How do they work?

Answer 35

- **NA** β2 adrenoreceptors in **detrusor** **muscle** (Gs-coupled), causing relaxation. - **NA** α1 adrenoreceptors in **sphincter** **muscle** (Gq-coupled) contraction. - Overall effect preventing urination.

Question 36

What is a drug involved in sympathetic activation of receptros in the bladder? How does it work?

Answer 36

**Prazosin** sympatholytic α1 antagonist that increases urinary flow by relaxing sphincter muscle - used particularly in benign prostatic hyperplasia.

Question 37

What is midriasis?

Answer 37

- Widening of the pupil. - Occurs in sympathetic activation of receptors in the eye. - Midriasis hinders intraocular fluid drainage.

Question 38

What is miosis?

Answer 38

- Pupil constriction. - Allows better near vision. - Occurs in parasympathetic activation of receptors in the eye. - Helps with intraocular fluid drainage.

Question 39

Which parasympathetic receptors are activated in the eye? How do they work?

Answer 39

- Gq-coupled ACh M3 muscarinic receptor circular iris muscle. → constriction of pupil (miosis) - Gq-coupled ACh M3 muscarinic receptors in ciliary muscle (sphincter muscle - contraction causes lens to bulge allowing better near vision).

Question 40

Which drugs are involved in parasympathetic activation of receptors in the eye? How do they work?

Answer 40

- **Atropine:** - parasympatholytic antagonist of M3 muscarinic receptors, eye drops to cause mydriasis and cycloplegia (paralysis of the ciliary muscle) for up to 7 days. Can be used in eye examinations. Recipients will struggle with focusing close up. - **Tropicamide:** (up to 6 hours - otherwise same as atropine action).

Question 41

Which receptors are activated by the SNS in the eye? How do they work?

Answer 41

- **NA** activates α1-adrenoreceptors (Gq-coupled) in the radial dilator pupillae muscle, leading to contraction, the pupil widens (**mydriasis**). - Useful in flight-or-flight as increases light sensitivity and gives a wider field of vision. - **NA** activates β-adrenoreceptors (Gs-coupled) in epithelium at ciliary body, stimulating increased production of intraocular fluid. - **NA** activates α1-receptors (Gq-coupled) in the iris radial muscle - mydriasis may hinders fluid drainage (iris is thicker). - Overall increased intraocular pressure (increased production of fluid and decreased drainage).

Question 42

What is glaucoma? How does it occur? How is it treated?

Answer 42

Glaucoma is chronically raised intraocular pressure above 21mmHg. Can damage optic nerve - potentially causing blindness. It results from imbalances in production and drainage of fluid in the eye. - **Pilocarpine**: muscarinic parasympathomimetic drug (lowers intraocular pressure). - **Timolol:** Non-selective β-adrenoreceptor antagonist (sympatholytic).