Pharmacology of the Autonomic Nervouse System II

Question 1

What is the problem with M3 cholinoceptor targetting drugs?

Answer 1

Drugs that act on the parasympathetic nervous system lack specificity. meaning they produce many side effects.

Limited number of drugs used clinically as a result.

Question 2

Which drug activates muscarinic cholinoceptors?

Answer 2

Pilocarpine

Question 3

Which drugs block muscarinic cholinoceptors?

Answer 3

Atropine

Tiotropium

Question 4

What other receptors are activated by M3 agonists?

Answer 4

M1, M2, and nicotinic receptors

Question 5

How are side-effects of muscarinic cholinoceptor agonists reduced? How is pilocarpine a good example of this?

Answer 5

Through topical administration.

Pilocarpine, for example is administered topically (via eye-drops) to the eyes to constrict pupil and promote drainage of aqueous humour thus reducing intraocular pressure.

Question 6

What condition can pilocarpine be used for?

Answer 6

Glaucoma, however it is not a first or second line treatment (beta blockers are a better idea).

Question 7

What is the most commonly used muscarinic receptor antagonist?

Answer 7

Atropine

Question 8

What receptors does atropine block?

Answer 8

Blocks all muscarinic cholinoceptor subtypes (muscarinic receptor antagonist

Question 9

What is the resulting physiological effect of atropine administration?

Answer 9

Dries up secretions (saliva, sweat, tears, gut, and lung)

Inhibits smooth muscle contraction (gut, lungs, eyes)

Increases heart rate (blocks M2)

Crosses into CNS to block muscarinic receptors creating excitatory effects (including restlessness, hyperactivity, and increased body temperature)

Question 10

What limits atropine use?

Answer 10

It is difficult to obtain organ selectivity without side effects.

Question 11

What problem is atropine commonly used for?

Answer 11

It is frontline therapy for poisoning with anticholinesterase agents (pesticides and war gases). This is because it blocks the muscarinic side effects.

Question 12

What is tiotropium used for?

Answer 12

COPD. It dilates the airways and reduces mucous secretion.

It is a long-acting drug (due to getting trapped within binding site without getting covalently attached) that is used for maintenance therapy rather than as a reliever.

Question 13

What does tiotropium do?

Answer 13

It is a muscarinic cholinoceptor antagonist. It is more selective than atropine for M3 receptor.

Question 14

How is tiotropium administered to COPD patients?

Answer 14

As an aerosol to avoid CNS effects

Question 15

What is tropicamide used for?

Answer 15

Short-term dilatation of eyes for clinical examination. (this drug is quite similar to tiotropium)

Question 16

What is solifenacin used for?

Answer 16

For urinary incontinence. (selective for the M3 receptor with less CVS side-effects)

Question 17

What do amphetamines do?

Answer 17

They block removal of noradrenaline from synaptic region.

Question 18

What does neostigmine do?

Answer 18

Blocks acetylcholine metabolism

Question 19

What happens when drugs alter neurotransmitter removal?

Answer 19

Increases synaptic levels of NT which results in increased activation of NT receptors and increased responses in effector cells.

Question 20

Describe the process of noradrenaline production and release from pre-synaptic neuron to post-synaptic neuron and what happens after nerve transmission at the synapse:

Answer 20

Tyrosine is hydroxylated to form DOPA and decarboxylated to form dopamine which sit in vesciles and is hydroxylated into noradrenaline.

NA then is released and acts on postsynaptic cell.

Noradrenaline transporter transports noradrenaline back into the neuron of the presynaptic neuron. (Neuronal reuptake) which halts signalling.

After beign taken up by presynaptic neuron the noradrenaline can be broken down via a monoamine oxidase which deactivates the noradrenaline.

Non-broken down noradrenaline is added to vesicles that are about to be released again.

Question 21

How does amphetamine interfere with noradrenaline signal transduction pathway?

Answer 21

Amphetamine is taken up from synapse via the same transporter as noradrenaline.

Amphetamine then blocks the monoamine oxydase which is responsible for breaking down noradrenaline

Amphetamine also induces reverse operation of noradrenaline transporter resulting in increased release of noradrenaline from the cell.

Increased noradrenaline in the junction stimulates adrenoceptors on effector cell resulting in increased sympathetic nerve activity

Question 22

Why is pseudoephedrine no longer used as a nasal decongestant?

Answer 22

It can be converted into methamphetamine.

Question 23

What is the use of amphetamine clinically?

Answer 23

CNS effects in children with ADHD

Question 24

What does pseudoephedrine do?

Answer 24

Increases amount of noradrenaline released from adrenergic nerves

Question 25

How does neurotransmission take place for cholinoceptors?

Answer 25

Cholinergic nerves synthesize and store acetylcholine

Upon stimulation nerves release acetylcholine which activates cholinoceptors on postsynaptic cells

Acetylcholine is then metabolised by enzyme AChE which terminates signalling by reducing [Ach] in region of cholinoceptor and instead converts acetylcholine into acetate and choline.

Question 26

What drugs take advantage of acetylcholine signal transmission pathway?

Answer 26

Acetylcholinesterase inhibitors such as neostigmine

Question 27

What are the major types of anticholinesterases?

Answer 27

Long-acting (act for days) due to irreversible covalent bond with active site. (eg. organophosphate pesticides and war gases) diagnosed via dumbbelss pneumonic.

Medium-acting (hours) such as neostigmine

Short-acting (minutes) such as edrophonium

Medium and short term are more clinically useful

Question 28

How can cholinergic overdose be diagnosed?

Answer 28

Dumbbelss

Diarrhoea
Urination
Miosis/muscle weakness
Bronchorrhea/Bronchoconstriction
Bradycardia
Emesis
Lacrimation
Salivation/Sweating
Seizures

Question 29

What kinds of conditions can be diagnosed and managed using acetylcholinesterase inhibitors?

Answer 29

Myasthenia gravis

Reversing neuromuscular blockade induced by non-depolarising neuromuscular blockers

Question 30

What is myasthenia gravis?

Answer 30

Condition that causes muscle weakness due to autoantibody activity against Nm receptors. This lost sensitivity can be overcome by increased acetylcholine in NMJ.

Question 31

What drug is commonly used to treat myasthenia gravis?

Answer 31

Neostigmine

Question 32

Where are neuromuscular blockers commonly used?

Answer 32

In general anaesthesia

Question 33

What are potential side effects in using neostigmine and other inhibitors of acetylcholinesterase?

Answer 33

Actions on the autonomic and central nervous systems