Drugs affecting neurotransmitters

Question 1

What is the action of BoTox (Botulinum toxin A)?

Answer 1

• modulates release of ACh by blocking vesicular exocytosis
• Tx: wrinkles, dystonia (e.g. blepharospasm/abnormal eye contraction), hyperhydrosis

Question 2

How does BoTox function?

Answer 2

• taken up selectively into cholinergic fibres
• light chain acts as a protease to cleave SNARE proteins
  
  • SNARE proteins on the outer synaptic vesicle interact with the neuronal membrane to trigger exocytosis
• tf blocks exocytosis of NT into the synaptic cleft

Question 3

How is AChE modulated?

Answer 3

• AChE inhibitors
• false substrates that mimick ACh
• bind to AChE active site, blocking degradation of ACh
• tf ACh acts in synaptic cleft for longer

Question 4

What are the differentiating properties of anticholinesterases?

Answer 4

• variable selectivity
  
  • NMJ (somatic) versus parasympathetic junctions
• variable CNS access (many cannot permeate BBB)
• variable duration of action
  
  • short, medium, irreversible

Question 5

Edrophonium

Answer 5

• short acting AChE
• used in Dx of myasthenia gravis

Question 6

Neostigmine/Pyridostigmine

Answer 6

• reverse effect of neuromuscular blockers
• used in Tx of myasthenia gravis

Question 7

Donepezil

Answer 7

• enters CNS
• used in Tx of Alzheimer’s (one of the few)

Question 8

What is myasthenia gravis?

Answer 8

• autoimmune disorder
• formation of Abs to own nicotinic receptors
• causes immune response and complement activation at NicRs and their site
  
  • flattens architecture of the NMJ (normally cilia-like)
  • cross-linking of 2 AChRs causing them to internalize on the postsynaptic membrane
  • [rare] autoAbs prevent ACh binding to NicRs

Question 9

How do anticholinesterases help in myasthenia gravis?

Answer 9

• blocks degradation of ACh so there is more in the synaptic cleft to activate the remaining ACh NicRs
  
  • early stage compensation
  • long-term lose more receptors and this method is ineffective
    
    • plasmaphoresis to try to remove Ab or immunosuppressive drugs to target underlying cause

Question 10

What is the Tensilon test?

Answer 10

• administration of edrophonium, short-acting AChE inhibitor to test myasthenia gravis as a cause of muscle weakness
  
  • if edrophonium relieves weakness, MG is likely cause

Question 11

What are Nm receptors?

Answer 11

• peripheral somatic nicotinic receptors
• cause contraction of skeletal muscle

Question 12

What are Nn receptors?

Answer 12

• peripheral neuronal nicotinic receptors of the ANS ganglia
• stimulate both ANS branches

Question 13

Nicotinic agonists are not typically used for

Answer 13

• peripheral disorders
• can be used for smoking cessation (e.g. patches)

Question 14

What are the clinical uses of nicotinic receptor antagonists?

Answer 14

• presurgical skeletal muscle relaxants (Nm selective)
  
  • e.g. non-depolarising forms tubocurarine/vecuronium
• ANS ganglion blockers (Nn selective) - rare and limited use
  
  • e.g. hexamethonium

Question 15

Agonist stimulation of ANS muscarinic receptors yields

Answer 15

• SLUD:
  
  • Salivation, Lacrimation, Urination, Defecation
• sweating
• bradycardia
• bronchoconstriction
• vasodilation (non-neural)

Question 16

What is an example of the clinical use of ANS muscarinic receptor agonists?

Answer 16

Pilocarpine for glaucoma Tx; reduces intra-occular pressure

Question 17

Antagonistic stimulation of ANS muscarinic receptors yields

Answer 17

dependent on level of PS tone

• reduced SLUD (Salivation, Lacrimation, Urination, Defecation)
• reduced sweating
• tachycardia - if fit, high PS dependence; if unfit, high SNS dependance tf no change
• bronchodilation

Question 18

What are some clinical uses of muscarinic antagonists?

Answer 18

• Atropine
  
  • reduce secretions triggered by anaesthesia (irritant) and produce bronchodilation pre-anaesthesia
  • bradycardia if driven by increased PS tone (unfit)
  • pupil dilation for retinal examination
  • AChE-inhibitor poisoning
• Hyoscine
  
  • motion sickness (CNS action)
• Ipratropium
  
  • COPD (inhaled)

Question 19

How can NA reuptake at the neuronal membrane be impeded?

Answer 19

• Cocaine and tricyclic antidepressents block mechanism (high-affinity uptake 1)
  
  • can increase HR and BP
• this increases NA in the synaptic cleft and stimulation of receptors downstream
• effect is mediated by CNS
  
  • similar mechanisms for uptake of dopamine and serotonin

Question 20

How can metabolism of NA inside the neuron be impeded?

Answer 20

• in sympathetic neurons monoamine oxidase (MAO) normally degrades NA released and re-uptaken by neuron
• MAO inhibitors lead to increased NA leak and +NA in the synaptic cleft
• commonly used as anti-depressents in the past

Question 21

What is the mechanism of indirectly actin sympathomimetics?

Answer 21

• taken up by the high-affinity Uptake 1 transporter on the sympathetic neuronal membrane similar to NA
• displace NA from synaptic vesicle storage
  
  • NA degraded by MAO or
  • released into cleft via transporter in reverse
• acting indirectly by displacing endogenous agonists, driving NA into the cleft

Question 22

What are examples of indirectly acting sympathomimetics?

Answer 22

• amphetamine
• ephedrine (pseudoephedrine)
• tyramine

Question 23

Ephedrine (pseudoephedrine)

Answer 23

• indirectly acting sympathomimetic
• used as nasal decongestant
• displaces NA in leaky, swollen nasal blood vessels
  
  • NA stimulates alpha-adrenoceptors on BV to constrict, reducing leakiness and swelling

Question 24

Tyramine

Answer 24

• indirectly acting sympathomimetic
• used as a dietary product (cheese, salami, vegemite)
• substrates for MAO
  
  • abundant in GIT, tf little reaches systemic circulation
  • if on MAO-inhibitors (depression), can cause unwanted cardio effects like tachycardia, hypertension

Question 25

Why is use of isoprenaline limited in asthma?

Answer 25

• Isoprenaline causes bronchodilation via beta-2 aRs, but also tachycardia via beta-1 aRs
• tf selective beta-2 aR agonist salbutamol is better, causes only the bronchodilation