L8. Drugs affecting Neurotransmitters Flashcards
How is drug modulation of the ACh pathway achieved? [2]
- Preventing exocytosis of the ACh vesicles
2. Facilitating ACh degradation
What is the consequence of ACh pathway drug inhibition?
Muscle paralysis if it is working at the neuromuscular junction.
What is the pathway of inhibiting ACh vesicle release. Give an example
Normal vesicle release of ACh requires the binding/complementary interaction of the ACh vesicle and SNARE proteins that are present on the cytosolic side of the membrane.
Attachment and interaction leads to a facilitated membrane fusion and exocytosis.
EG. BoTox: used cosmetically mainly is a protease enzyme that cleaves snare proteins and prevents this complimentary binding. As an enzyme, only minute amounts of the toxin are required to cause a large scale inhibition.
What is the pathway of inhibiting ACh degradation?
Acetylcholinesterases in the cleft breakdown ACh and by inhibiting these enzymes, we can extend the duration and force of action of ACh in the cleft.
These drugs have variable selectivity, CNS access and durations of action depending on the type of drug (short, medium or irreversible)
What are some examples of Acetylcholinesterase inhibitors?
Edrophonium: short duration of action and used in the tensilon test for MG
Noestigmine/Pyriostigmine: reverse effects of neuromuscular blockers and in treatment of MG
Donepezil: enters the CNS well and is used in alzheimer’s disease
What is myasthenia gravis?
An autoimmune disease where antibodies are raised against the nicotinic cholinergic receptors of the neuromuscular junction (Nm skeletal muscle). This means antibodies bind to the receptors and cross link them causing an endocytosis of them.
Progressive disease that degrades the post-synaptic membrane leading to Reduced skeletal muscle contraction = paralysis.
What are the Nicotinic cholinergic receptors for and where are they located?
In both the somatic and the autonomic nervous system. There are two types:
Nm (skeletal muscles)
Nn (ganglionic) causing a number of effects
What are some examples and uses of agonists and antagonists of the nicotinic receptor?
Agonist: nicotine: smoking cessation
Antagonist: Pre-surgical muscle relaxants and sometimes ganglionic blockage (rare)
What are the Muscarinic cholinergic receptors for and where are they located?
Parasympathetic (rest and digest) receptors
M1,4,5 - CNS
M2 - heart
M3 - smooth muscle
Parasympathetic: SLUD:
Sweating, lacrimation, urination and defecation as well as bradycardia, vasodilation
What are some examples and uses of agonists and antagonists of the muscarinic receptor?
Agonists: Pilocarpine (used to vasodilate the vessels of the eyes in glaucoma)
Antagonists: depends on the level of sympathetic tone
Atropine: reduces secretions and production of bronchodilation
Hyoscine: motion sickness
Ipatropium: COPD
What are the three methods of modulating (decreasing) adrenergic stimulation?
- Blockage of the Neuronal High affinity Uptake Receptor-1
- Blockage of metabolism of noradrenaline
- Indirectly acting sympathomimetics
How does the blockage of neuronal high affinity uptake 1 occur?
Leads to an overall enhanced level of noradrenaline in the synapse
EG. Cocaine and other tricyclic antidepressants leading to increased dopamine and noradrenaline in the CNS as well as tachycardia and hypertension in the periphery.
How is adrenaline metabolised once it is retaken up by the NHAU-1 receptor?
When Adrenaline (and noradrenaline and dopamine) are taken back up into the cell, they are either repackaged into vesicles or the enzyme Monoamine Oxidase (MAO) from the mitochondria breaks it down into metabolites. These metabolites ensure than any unpackaged adrenaline leaks out into the cell.
How is the MOA pathway used to modulate actions of adrenaline?
Inhibition of MOA actions means that there is an less degradation and more NA is allowed to leave the cell and cause a higher action.
What is an indirectly sympathomimetic? Give some examples
Sympathomimetics mimic the action of adrenaline or noradrenaline and cause the release of adrenaline into the synapse in a non-exocytotic mechanism.
Eg. Amphetamine, epherine and tyramine
