How does organophosphates cause dyspnea? Please, and I mean please be incredibly

Question

How does organophosphates cause dyspnea? Please, and I mean please be incredibly specific. Just telling me acetylcholine(ACh) is built up due to the fact the organophosphates stop acetylcholinase from breaking down ACh is not good enough. How does acetylcholine SPECIFICALY mess with ones breathing?

Please tell me how organophosphates specifically cause dyspnea. Step 1 blank, step 2 blank, step 3 blank ...Step etc until youve described the mechanism.. The last 4 attempts to get a precise answer have failed :(

Explanation / Answer

Organophosphates are anti-esterase insecticides that over stimulate cholinergic nerve stimulus.

Acetylcholinesterase (AChE) is the enzyme that degrades neurotransmitter acetylcholine in the synapse. It is found between the synapse between nerve cell and muscle cell. This enzyme works only when the signal is passed to break down the neurotransmitter to prevent excessive signaling.

Ach is expressed by central and peripheral nervous system, red blood cells and neuromuscular junctions.

When a nerve impulse is released, acetylcholine is released in the synapse of the nerve cell with the muscle cell. Acetylcholinesterase breaks down acetylcholine into acetic acid and choline.

Organophosphates phosphorylate acetylcholinesterase and reduce its ability to bind acetylcholine.

Mechanism of Action:

1) Organophosphates enter the circulation by cutaneous absorption, ingestion, inhalation, or injection route. Severity of the damage depends on the organophosphate, the route of administration, and rate of metabolic degradation.

2) Organophosphates of the phosphorothionate esters (P=S) variety are generally poor anticholinesterases due to lesser polarization of their P=S linkages as compared to their P=0 linkages. (Sulfur is less electronegative than O). However, upon entry in the body, P=S bond is converted to P=0 occurs creating a more electropositive phosphorus atom. This metabolic reaction is carried out by the ubiquitous enzyme called mixed function oxidase (MFO). As a result, a poor anticholinesterase is converted to a strong anticholinesterase. Another step that can occur is the metabolic oxidation of the thioester moiety on the organophosphates to sulfoxide and finally to sulfone.

3) The metabolic activation of the P=S to P=) allow attack of the phosphorous by the serine hydroxyl group of AChE. A chemical reaction occurs by which serine hydroxyl moiety in the enzyme active site is phosphorylated. This phosphorylation is analogous to the normal acetylation of AChE. However, the phosphorylated AChE by organophosphates is extremely stable and in most instances, depending on type of organophosphate, is irreversibly inhibited. Since the serine hydroxyl group is blocked by the phosphoryl moiety of organophosphate, it can no longer participate in hydrolysis of acetylcholine (Ach).

4. Binding of organophosphates to AChE cause three changes to the enzyme:

a) There is endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases

b) Reactivation of the enzyme can occur by a strong nucleophile such as pralidoxime (2-PAM)

c) Irreversible binding by the insecticide can cause permanent enzyme inactivation. Phosphorylation is causes loss of an organophosphate leaving group. The bond with AChE and organophosphates therefore becomes irreversible, a process called aging.

5. Breakdown of AChE causes accumulation of Ach in the central nervous system. As a result, there is overstimulation of muscarinic and nicotinic receptors.

6) Effects on muscarinic receptors include miosis, hypersalivation, nausea, emesis, bronchospasm, bronchorrhea, alveolar edema, bradycardia, and hypotension. The nicotinic effects include sweating, muscle weakness, fasciculations, and paralysis, occasionally with hypertension and tachycardia.

7) The overstimulation of muscarinic receptors cause delayed neuromuscular dysfunction, and recurrent cholinergic toxicity. Stimulation of musarinhic M3 receptor causes contraction of bronchial smooth muscle resulting in bronchospasm. Nicotinic and M2 receptors are also involved. The pulmonary endothelial barriers are also disrupted. There may be indirect or direct disruption of alveoli.

8) The exact mechanism by which OP (organophosphates) cause dyspnea are unclear. However, for all these effects to be seen, the mechanism has to be central respiratory distress. Excess acetylcholine may affects the function of the Pre-Boetzinger complex depressing respiratory activity. The Pre-Boetzinger complex is present in the ventrolateral medulla, which is under the control of glutamanergic and muscarinic receptors. Severe overstimulation of the muscarinhic receptors ultimately leads to dyspnea, which is shortness of breath or complete respiratory failure.

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