W7: Pharmacology Of The ANS

Question 1

What does hexamethonium do?

Answer 1

Selective antagonist for the neuronal subtype of nicotinic receptor (not at the NMJ). Not competitive and blocks all effects of autonomic stimulation.

Question 2

Where do you find muscarinic receptors?

Answer 2

At parasympathetic postganglionic synapses

Question 3

What effects to parasympathomimetics have?

Answer 3

Mimic effects of the parasympathetic nerve stimulation acting as muscarinic agonists
Cardiovascular - decreased HR and CO
Smooth muscle - contracts (vascular smooth muscles dilate via endothelial influences so difficult to predict)
Exocrine glands - secrete - e.g., sweating, lacrimation, salivation, bronchial secretion

Question 4

Examples of muscarinic agonists

Answer 4

ACh, muscarine, pilocarpine

Question 5

What are the effects of muscarine poisoning?

Answer 5

Adverse effects (same symptoms of muscarinic activation):

• bradycardia, vasodilation (secondary to NO), so fall in BP
• increased gut motility, bronchoconstriction, pupillary constriction
• salivation, lacrimation, airway secretions

Question 6

What is the source and treatment of muscarine poisoning?

Answer 6

Source: Many mushrooms
Treatment: Muscarinic antagonist - atropine

Question 7

What is pilocarpine (muscarinic agonist) used for?

Answer 7

To treat glaucoma

Question 8

How is pilocarpine administered?

Answer 8

Topically applied to the eye

Question 9

What is the action of pilocarpine?

Answer 9

Acts on M3 receptors on ciliary muscles improving aqueous humor drainage, dropping intra-ocular pressure.

Question 10

Common muscarinic antagonists

Answer 10

Less specific ones, e.g., atropine, hyoscine

Question 11

Clinical uses of antimuscarinic drugs (muscarinic antagonists)

Answer 11

• asthma - PNS causes narrowing of airways so antagonists reverse
• treatment of bradycardia - PNS causes slower HR, so blocking this speeds HR
• to decrease gut motility
• to decrease secretions during operations
• dilate pupils
• urinary incontinence
• motion sickness - there are lots of muscarinic receptors in the enteric NS

Question 12

What do activated alpha1 adrenoceptors do?

Answer 12

Contract smooth muscle (e.g., vasoconstriction)

Question 13

What do alpha2 adrenoceptors do?

Answer 13

Pre-synaptic auto-inhibition, direct vasoconstriction, central inhibition of sympathetic outflow

Question 14

What do beta1 adrenoceptors do?

Answer 14

Increase heart rate and contractility

Question 15

What do beta2 adrenoceptors do when activated?

Answer 15

Relax smooth muscle (bronchodilation, vasodilation)

Question 16

What do beta3 receptors do when activated?

Answer 16

Relax smooth muscle (bladder); stimulate lipolysis

Question 17

What are the main uses of alpha receptor agonists

Answer 17

Vasoconstrictors with LA (mainly alpha1)
Nasal decongestants (mainly alpha 1)
Hypertension (central alpha2)
Facial erythema in rosacea (alpha2)

Question 18

How does adrenaline work in LA?

Answer 18

Adrenaline causes a local vasoconstriction, contracting smooth muscles meaning the licocaine (LA) stays where it is put, causing a better action.

Question 19

How does NA cause alpha adrenoceptor activation?

Answer 19

NA binds to g-protein coupled receptors
Alpha receptor uses the Gq protein, which is linked to phospholipase C
Phospholipase C produces DG and IP3
IP3 mediates effects on smooth muscle, activating its receptor (ligand-gated ion channel) found on the ER. Allows Ca2+ out of the ER to cause contraction, so constrict blood vessels.
Does not have to cross a membrane to activate the receptor

Question 20

What is the G-protein, target and transduction effect for alpha1 adrenoceptor?

Answer 20

Gq
PLC
Increased production of IP3/DAG

Question 21

What is the G-protein, target and transduction effect for alpha2 adrenoceptor?

Answer 21

GI
Decreased AC
Decreased cAMP

Question 22

What is the G-protein, target and transduction effect for beta adrenoceptors?

Answer 22

Gs
Increased AC
Increased cAMP

Question 23

What is the G-protein, target and transduction effect for M1, M3?

Answer 23

Gq
PLC
Increased IP3/DAG

Question 24

What is the G-protein, target and transduction effect for M2 receptors?

Answer 24

Gi
Decreased AC
Decreased cAMP

Question 25

Main uses of beta-receptor agonists with examples

Answer 25

Mimic the action of sympathetic activation (NA released from sympathetic nerve terminals)

• cardiogenic shock (beta1) - e.g, adrenaline
• anaphylactic shock (alpha/beta) - e.g., adrenaline
• asthma (beta2) - e.g., salbutamol

Question 26

Main uses of alpha antagonists

Answer 26

Reversing sympathetic symptoms

• hypertension (alpha1 - dozazosin)
• benign prostate hyperplasia (alpha1 - tamsulosin)

Question 27

How does a largened prostate affect the bladder?

Answer 27

Large prostate will press on urethra, causing bladder problems. Alpha antagonists reduces contraction of the prostate.

Question 28

Main beta antagonists

Answer 28

Propranolol (beta1/2)

Metaprolol (beta1)

Question 29

Main uses of beta antagonists

Answer 29

Beta 1 specific to the heart - to treat heart problems like angina, cardiac arrhythmias, hypertension
Treat anxiety states, chronic heart failure
Locally glaucoma - SNS would dilate the pupil so the antagonist would constrict the pupil

Question 30

Uptake 1: what happens to noradrenaline once it’s released?

Answer 30

Once released, it is taken back up into the nerve terminal by noradrenaline transporter NAT (a secondary active transporter), to terminate its actions
Relatively selective for NAd

Question 31

What does NAT cotransport?

Answer 31

Na+, Cl-, catecholamines

Question 32

What is the NAT transporter inhibited by?

Answer 32

Cocaine, tricyclic antidepressants (desipramine)

Question 33

What is the effect or NAT inhibitors?

Answer 33

They enhance the effects of sympathetic activity

Question 34

What transporters is NAT closely related to?

Answer 34

Dopamine and serotonin transporters, DAT and SERT

Question 35

What happens to DAT and SERT if NAT is inhibited

Answer 35

These ‘reward’ neurotransmitters, dopamine and serotonin, you will amplify the effect of their transmission centrally, producing pleasure.

Question 36

What are the effects of desipramine?

Answer 36

A tricyclic antidepressant. Major action is on the CNS. Adverse effects: tachycardia, dysrhythmia (abnormal heart rhythms)

Question 37

What are the effects of cocaine?

Answer 37

Euphoria and excitement (CNS action)
Causes tachycardia by increased drive to the heart and increased BP by causing peripheral vasoconstriction (peripheral)
Can be used as a local anaesthetic (by inhibition of Na+ channels)

Question 38

What do mono-amine oxidase inhibitors do?

Answer 38

Block MAO irreversible

Increases levels of noradrenaline, dopamine, 5-HT, in the brain and peripheral tissues

Question 39

What is the clinical use of MAO inhibitors?

Answer 39

Antidepressants

Question 40

What does MAO do?

Answer 40

Terminates the action of NA by breaking it down

Question 41

Adverse effects of MAO inhibitors

Answer 41

Postural hypotension, weight gain, restlessness, insomnia, cheese reaction (hypertensive episode following ingestion of tyramine-containing food, e.g., cheese; flushing)

Question 42

Examples of MAO inhibitors

Answer 42

Phenelzine, moclobemide (reversible competitive inhibitor)

Question 43

Give examples of indirectly acting sympathetic amines and what are they structurally related to?

Answer 43

Amphetamine, tyramine

Structurally related to adrenaline

Question 44

Why are indirectly acting sympathetic amines indirectly acting?

Answer 44

Because they do not directly affect a receptor
They are transported into nerve terminals via NAT and into vesicles by VMAT, mimicking the route of NA
They displace NA, which leaks out via NAT, producing sympathetic like effects

Question 45

What are the effects of indirectly acting sympathetic amines?

Answer 45

Long-lasting effects that mimic those of NA (sympathetic NS effects).
Bronchodilation, vasoconstriction, positive inotropy, raised BP