ANS Flashcards
Evidence of neurohumoral transmission
it should be present in the presynaptic neurone usually along with enzymes synthesizing it.
It should be released in the medium following nerve stimulation
Its application should produce responses identical to those produced by nerve stimulation
Its effects should be antagonised or potentiated by other substance which similarly alter effects of nerve stimulation.
Demonstration of enzyme or mechanism for the termination of its effect.
SYNTHESIS OF ACETYCHOLINE
Biosynthesis of Acetylcholine in cholinergic neurones is caused by the acetylation of choline derived from diet or hydrolysis of acetylcholine.
This reaction is catalyzed by choline acetyl transferase with acetyl co-enzyme A serving as the acetyl donor
Choline available in the diet and those ones derived from the hydrolysis of acetylcholine are actively taken up into the axonal membrane by high affinity choline uptake process.
The rate limiting step in the synthesis is the choline transport or availability of choline.
Drugs that compete with choline for transport into cholinergic neurones block its uptake and inhibit synthesis of Ach e.g. hemicholinium, triethylcholine
Drugs like botulinum toxin block propagation of action potential (A.P) along the neurone thereby inhibiting the entire process of neurochemical transmission
STORAGE & RELEASE
Once synthesized, it is transported from the cytoplasm into the vesicles to be stored; when action potential reaches the terminal and the latter undergoes stimulation, acetylcholine is released to the synaptic cleft.
METABOLISM
After release from the presynaptic terminal the molecule binds to and activates an acetylcholine receptor (cholinergic receptor) located on effector cell.
Finally, it is hydrolyzed into choline and acetate by acetyl cholinesterase enzyme which terminates its action.
Choline is taken back into the neurone for synthesis of more Ach.
Two types of cholinesterase enzyme exist
Acetyl cholinesterase found in closed association with cholinergic neurones. It terminates the action of the released Ach from the nerve ending.
Butyl cholinesterase or pseudo-cholinesterase found in the plasma, liver. It inactivate Ach and other choline esters present in circulation and other parts of the body.
Proposed site of action of drugs on the synthesis, action, and fate of ACh at parasympathetic neuroeffector junctions
vesamicol- inhibits the transport of Ach from the cytoplasm to the vesicle
hemicholium- competes with choline for transport into cholinergic neurones block its uptake and inhibit synthesis of Ach
botulinum toxin- block propagation of action potential (A.P) along the neurone thereby inhibiting the entire process of neurochemical transmission
AChE Inhibitors- inhibit the activity of Ach esterase
DISTRIBUTION OF MUSCARINIC RECEPTORS
check note
There are two groups of cholinergic drugs:
Direct-acting:
bind to and activate muscarinic or nicotinic receptors (mostly both) and include the following subgroups:
. Esters of choline and synthetic esters :
Acetylcholine; methacholine, carbachol, bethanechol
b. Cholinergic alkaloids:
Pilocarpine, muscarine, arecoline, nicotine
Indirect-acting:
inhibit the action of acetylcholinesterase enzyme also called anticholinesterases.
They are:
Reversible: neostigmine, physostigmine, edrophonium
Irreversible: Organophosphate compounds e.g. echothiopate, parathion, malathion, sarin, soman
Other synthetic choline esters
Metacholine, Carbachol and Bethanechol.
These drugs have the following advantages over ACh:
* they have longer duration of action,
* they are effective orally as well as parenterally, and
* they are relatively more selective in their actions
Nicotinic antagonists
ANTICHOLINERGICS/ ANTIMUSCARINICS/MUSCARINIC ANTAGONISTS
Nicotinic antagonists also block certain action of Ach, they are generally referred to as ganglion blockers (hexamethonium, trimethaphan ) and neuromuscular blockers (tubocurarine, pancuronium)
There are three closely related endogenous catecholamines (CAs)
Examples of catecholamines are:
Adrenaline
Noradrenaline
Dopamine
THE SYNTHESIS, STORAGE AND RELEASE OF CATECHOLAMINES
The main pathway for the synthesis of catecholamines was first postulated by Blaschko (1939).
The starting point for the synthesis of catecholamines is from the essential amino acid phenyl alanine or from tyrosine, which are found in the protein in the diet.
Usually the dietary intake of tyrosine is adequate for catecholamine synthesis.
It can also be obtained from phenylalanine by the effect of the enzyme phenylalanine hydroxylase.
The tyrosine is actively transported into the axoplasm and is converted to DOPA by the enzyme tyrosine hydroxylase.
DOPA is converted to Dopamine by DOPA decarboxylase. All these take place within the cytoplasm of the adrenergic neurone.
The dopamine is transported into the storage vesicles where it is converted to noradrenaline by the enzyme Dopamine β- hydroxylase.
The enzyme tyrosine hydroxylase requires tetrahydropteridine, oxygen and ferrous ion (Fe)
DOPA decaborxylase requires pyridoxal phosphate.
Dopamine hydroxylase requires ascorbic acid and copper ions.
whats the rate limiting step what enzyme catalyzes it and what does the enzyme require? what its inhibited by?
The hydroxylation of tyrosine to DOPA is the rate limiting step in the biosynthesis of catecholamines and it is a relatively slow process.
Tyrosine hydroxylase is a specific and the rate limiting enzyme.
The enzyme tyrosine hydroxylase requires tetrahydropteridine, oxygen and ferrous ion (Fe)
Its inhibition by α-methyl-p-tyrosine results in depletion of CAs.
This inhibitor can be used in pheochromocytoma before surgery and in inoperable cases.
STORAGE OF CATECHOLAMINES
The catecholamines are stored in storage vesicles located in the never terminals
The vesicles have been shown to have high concentration of catecholamines which are bound to ATP in the ratio 4:1
The storage also contain chromograins, dopamine hydroxylase, ascorbic acid and enkephalin precursor
Some substances produce their pharmacological effect by displacing catecholamines from the storage vesicles and therefore cause the release of noradrenaline in the adrenergic nerve terminals.
These substance are referred to as indirectly acting sympathomimetic amines e.g. tyramine, ephedrine, amphetamine etc.
Storage pools exist for noradrenaline:
Pool I (labile pool)- rapid turn over
Pool II (fixed pool)- slow turn over
In the storage vesicle, NA occurs in free unbound form and bound form
Free NA occurs in equilibrium with the one that is bound with ATP.
Outside the vesicle, NA is also present in the free form i.e. within the cytoplasm.
The free unbound NA within the cytoplasm may play an important role in the regulation of catecholamine synthesis by means of end product inhibition of tyrosine hydroxylase
