Cholinergic System and Drugs

 Chapter -7 

Cholinergic System and Drugs

CHOLINERGIC TRANSMISSION

Acetylcholine (Ach) is a major neurohumoral transmitter at autonomic, somatic as well as central sites.

Synthesis, storage and destruction of Ach

The cholinergic neuronal mechanisms are summarized in Acetylcholine is synthesized locally in the cholinergic nerve endings by the following pathway

ACETYLCHOLINE CHLORIDE

• Choline is actively taken up by the axonal membrane by a Na+: choline cotransporter and acetylated with the help of ATP and coenzyme-A by the enzyme choline acetyl transferase present in the axoplasm. Hemisodium blocks choline uptake (the rate limiting step in Ach synthesis) and depletes Ach. Most of the Ach is stored in ionic solution within small synaptic vesicles, but some free Ach is also present in the cytoplasm of cholinergic terminals. Active transport of Ach into synaptic vesicles is affected by another carrier which is blocked by Vesa Micol.

• Release of Ach from nerve terminals occurs in small quanta—amount contained in individual vesicles is extruded by exocytosis. In response to a nerve AP synchronous release of multiple quanta triggers postjunctional events.

• Two toxins interfere with cholinergic transmission by affecting release: botulinus toxin inhibits release, while black widow spider toxin induces massive release and depletion. Immediately after release, Ach is hydrolyzed by the enzyme cholinesterase and choline is recycled.

• A specific (Acetylcholinesterase—Ache or true cholinesterase) and a nonspecific (Butyrylcholinesterase—Buche or pseudocholinesterase) type of enzyme occurs in the body; important differences between these two types are given in Table 7.2. While Ache is strategically located at all cholinergic sites and serves to inactivate Ach instantaneously, Buche present in plasma and elsewhere probably serves to metabolize ingested esters.

Cholinoceptors

Two classes of receptors for Ach are recognized —muscarinic and nicotinic; the former is a G protein coupled receptor, while the latter is a ligand gated cation channel.

• Muscarinic These receptors are selectively stimulated by muscarine and blocked by atropine. They are located primarily on autonomic effector cells in heart, blood vessels, eye, smooth muscles and glands of gastrointestinal, respiratory and urinary tracts, sweat glands, etc. and in the CNS. Subsidiary muscarinic receptors are also present in autonomic ganglia where they appear to play a modulatory role by inducing a long-lasting late EPSP.

• Muscarinic auto receptors are present prejunctional Ly on postganglionic cholinergic nerve endings: their activation inhibits further Ach release. Similar ones have been demonstrated on adrenergic terminals: their activation inhibits NA release (may contribute to vasodilator action of injected Ach). All blood vessels have muscarinic receptors (though most of them lack cholinergic innervation) located on endothelial cells whose activation releases EDRF which diffuses to the smooth muscle to cause relaxation.

• Subtypes of muscarinic receptor by pharmacological as well as molecular cloning techniques, muscarinic receptors have been divided into 5 subtypes M1, M2, M3, M4 and M5. The first that are present on effector cells as well as on prejunctional nerve endings and are expressed both in peripheral organs as well as in the CNS. The M4 and M5 receptors are present mainly on nerve endings in certain areas of the brain and regulate the release of other neurotransmitters. Functionally, M1, M3 and M5 fall in one class while M2 and M4 fall in another class. Muscarinic agonists have shown little subtype selectivity, but antagonists (pirenzepine for M1, trimipramine for M2 and darifenacin for M3) are more selective. Most organs have more than one subtype, but usually one subtype predominates in a given tissue.

• M1: The M1 is primarily a neuronal receptor located on ganglion cells and central neurons, especially in cortex, hippocampus and corpus striatum. It plays a major role in mediating gastric secretion, relaxation of lower esophageal sphincter (LES) on vagal stimulation and in learning, memory, motor functions, etc.

• M2: Cardiac muscarinic receptors are predominantly M2 and mediate vagal bradycardia. Auto receptors on cholinergic nerve endings are also of M2 subtype. Smooth muscles express some M2 receptors as well which, like M3, mediate contraction

• M3: Visceral smooth muscle contraction and glandular secretions are elicited through M3 receptors, which also mediate vasodilatation through EDRF release. Together the M2 and M3 receptors mediate most of the well-recognized muscarinic actions including contraction of LES.

• The muscarinic receptors are G-protein coupled receptors having the characteristic 7 membrane traversing amino acid sequences. The M1 and M3 (also M5) subtypes function through GQ protein and activate membrane bound phospholipase C (Plc.)—generating inositol trisphosphate (IP3) and diacylglycerol (DAG) which in turn release Ca2+ intracellularly—cause depolarization, glandular secretion and raise smooth muscle tone. They also activate phospholipase A2 resulting in enhanced synthesis and release of prostaglandins and leukotrienes in certain tissues. The M2 (and M4) receptor opens K+ channels (through βγ subunits of regulatory protein Gi) and inhibits adenylyl cyclase (through α subunit of Gi) resulting in hyperpolarization, reduced pacemaker activity, slowing of conduction and decreased force of contraction in the heart. The M4 receptor has been implicated in facilitation/ inhibition of transmitter release in certain areas of the brain, while M5 has been found to facilitate dopamine release and mediate reward behavior.

• Nicotinic These receptors are selectively activated by nicotine and blocked by tubocurarine or hexamethonium. They are rosette-like pentameric

• structures (see Fig. 4.4) which enclose a ligand gated cation channel: their activation causes opening of the channel and rapid flow of cations resulting in depolarization and an action potential. On the basis of location and selective agonists and antagonists two subtypes NM and NN (previously labelled N1 and N2) are recognized.

• NM: These are present at skeletal muscle endplate: are selectively stimulated by phenyl trimethyl ammonium (PTMA) and blocked by tubocurarine. They mediate skeletal muscle contraction.

• NN: These are present on ganglionic cells (sympathetic as well as parasympathetic), adrenal medullary cells (embryologically derived from the same site as ganglionic cells) and in spinal cord and certain areas of brain. They are selectively stimulated by dimethyl phenyl piperidinium (DMPP), blocked by hexamethonium, and constitute the primary pathway of transmission in ganglia.

CHOLINERGIC DRUGS
(Cholinomimetic, Parasympathomimetic)

These are drugs which produce actions similar to that of Ach, either by directly interacting with cholinergic receptors (cholinergic agonists) or by increasing availability of Ach at these sites (anticholinesterases).

A. Muscarinic

Heart Ach hyperpolarizes the SA nodal cells and decreases the rate of diastolic depolarization. As a result, rate of impulse generation is reduced bradycardia or even cardiac arrest may occur.

• At the A-V node and His-Purkinje fibers refractory period (RP) is increased and conduction is slowed: P-R interval increases and partial to complete A-V block may be produced. The force of atrial contraction is markedly reduced, and RP of atrial fibers is abbreviated. Due to nonuniform vagal innervation, the intensity of effect on RP and conduction of different atrial fibers varies— inducing inhomogeneity and predisposing to atrial fibrillation or flutter.

• Ventricular contractility is also decreased but the effect is not marked. The cardiac muscarinic receptors are of the M2 subtype.

Blood vessels All blood vessels are dilated, though only few (skin of face, neck, salivary glands) receive cholinergic innervation. Fall in BP and flushing, especially in the blush area occurs. Muscarinic (M3) receptors are present on vascular endothelial cells: vasodilatation is primarily mediated through the release of an endothelium dependent relaxing factor (EDRF) which is nitric oxide (NO). It may also be due to inhibitory action of Ach on NA release from tonically active vasoconstrictor nerve endings.

• Stimulation of cholinergic nerves to the penis causes erection by releasing NO and dilating caver Nosal vessels through M3 receptors. However, this response is minimal with injected cholinomimetic drugs.

Smooth muscle Smooth muscle in most organs is contracted (mainly through M3 receptors). Tone and peristalsis in the gastrointestinal tract is increased and sphincters relax → abdominal cramps and evacuation of bowel.

• Peristalsis in ureter is increased. The detrusor muscle contracts while the bladder trigone and sphincter relax → voiding of bladder.

• Bronchial muscles constrict, asthmatics are highly sensitive → dyspnea, precipitation of an attack of bronchial asthma.    

Glands Secretion from all parasympathetically innervated glands is increased via M3 and some M2 receptors: sweating, salivation, lacrimation, tracheobronchial and gastric secretion. The effect on pancreatic and intestinal glands is not marked. Secretion of milk and bile is not affected.

Eye Contraction of circular muscle of iris → miosis. Contraction of ciliary muscle → spasm of accommodation, increased outflow facility, reduction in intraocular tension (especially in glaucomatous patients).

B. Nicotinic

• Autonomic ganglia Both sympathetic and parasympathetic ganglia are stimulated. This effect is manifested at higher doses. High dose of Ach given after atropine causes tachycardia and rise in BP due to stimulation of sympathetic ganglia and release of catecholamines.

• Skeletal muscles Iontophoretic application of Ach to muscle endplate causes contraction of the fiber. Intraarterial injection of high dose can cause twitching and fasciculations, but i.e. injection is generally without any effect (due to rapid hydrolysis of Ach).

C. CNS

Ach injected i.e., does not penetrate blood-brain barrier and no central effects are seen. However, direct injection into the brain, or other cholinergic drugs which enter brain, produce a complex pattern of stimulation followed by depression.

• Interactions Anticholinesterases potentiate Ach markedly, methacholine to less extent and have only additive action with carbachol or bethanechol, depending upon the role of ChE in the termination of action of the particular choline ester. Atropine and its congeners competitively antagonize muscarinic actions.

• Uses Choline esters are rarely, if ever, clinically used. Ach is not used because of evanescent and nonselective action. Methacholine was occasionally used to terminate paroxysmal supraventricular tachycardia but is obsolete now.

• Bethanechol has been used in postoperative/ postpartum nonobstructive urinary retention, neurogenic bladder, congenital megacolon and gastroesophageal reflux. Side effects are prominent: belching, colic, involuntary urination/ defecation, flushing, sweating, fall in BP, bronchospasm.

CHOLINOMIMETIC ALKALOIDS

• Pilocarpine It is obtained from the leaves of Pilocarpus microphyllus and other species. It has prominent muscarinic actions and also stimulates ganglia—mainly through ganglionic muscarinic receptors.

• Pilocarpine causes marked sweating, salivation and increases other secretions as well. The cardiovascular effects are complex. Small doses generally cause fall in BP (muscarinic), but higher doses elicit rise in BP and tachycardia which is probably due to ganglionic stimulation (through ganglionic muscarinic receptors). Applied to the eye, it penetrates cornea and promptly causes miosis, ciliary muscle contraction and fall in intraocular tension lasting 4–8 hours.

• Pilocarpine is used only in the eye as 0.5–4% drops. It is a third-line drug in open angle glaucoma. An initial stinging sensation in the eye and painful spasm of accommodation are frequent side effects. Other uses as a miotic are— to counteract mydriatics after they have been used for testing refraction and to prevent/break adhesions of iris with lens or cornea by alternating it with mydriatics.

• Muscarine, It occurs in poisonous mushrooms Amanita muscaria and Inouye species and has only muscarinic actions. It is not used therapeutically but is of toxicological importance.

• Mushroom poisoning Depending on the toxic principal present in the particular species, at least 3 types of mushroom poisoning is known.

• Muscarine type (Early mushroom poisoning) due to Inouye and related species. Symptoms characteristic of muscarinic actions appear within an hour of eating the mushroom and are promptly reversed by atropine.

• Hallucinogenic type It is due to muscimol and other isoxazole compounds which are present in A. muscaria and related mushrooms in much larger quantities than is muscarine. These compounds activate amino acid receptors and block muscarinic receptors in the brain; have hallucinogenic property. Manifestations of poisoning are primarily central. There is no specific treatment and atropine is contraindicated. Another hallucinogenic mushroom is Psilocybin Mexicana whose active principal psilocybin is a Tryp aminergic (5-HT related) compound.

• Phalloidin type (Late mushroom poisoning) It is due to peptide toxins found in A. phalloides, Ballerina and related species. These inhibit RNA and protein synthesis. The symptoms start after many hours and are due to damage to the gastrointestinal mucosa, liver and kidney. Treatment consists of supportive measures. Theistic acid may have some antidotal effect. 

• Arecoline It is found in betel nut Areca catechu and has muscarinic as well as nicotinic actions, including those on skeletal muscle endplate. It also has prominent CNS effect: has been tried in dementia as an enhancer of cognitive functions, but not found useful—has no therapeutic use.

ANTICHOLINESTERASES

• Anticholinesterases (anti-ChEs) are agents which inhibit ChE, protect Ach from hydrolysis—produced cholinergic effects in vivo and potentiate Ach both in vivo and in vitro. Some anti ChEs have additional direct action on cholinergic receptors.

MECHANISM OF ACTION

• The anti-ChEs react with the enzyme essentially in the same way as Ach. The carbamates and phosphates respectively carbamylate and phosphorylated the eustatic site of the enzyme.

• The mammalian Ache has been cloned and details of its structure as well as mode of interaction with Ach and various anti-ChEs has been worked out.

• The active region of Ache forms a gorge which contains an aromatic anionic site (near tryptophan 86) and an ecstatic site formed by serine 203, glutamate 334, histidine 447 (Fig. 7.2A). Hydrolysis of Ach involves electrostatic attraction of positively charged N+ of Ach to the aromatic pocket (Fig. 7.2B) and nucleophilic attack by serine-OH which is activated by the adjacent histidine leading to acetylation of serine (Fig. 7.2C). The acetylated enzyme reacts with water to produce acetic acid and choline (Fig. 7.2D).

• Whereas the acetylated enzyme reacts with water extremely rapidly and the ecstatic site is freed in a fraction of a millisecond, the carbamylated enzyme (reversible inhibitors) reacts slowly (Fig. 7.2E, F) and the phosphorylated enzyme (irreversible inhibitors) reacts extremely slowly or not at all (Fig. 7.2G). It is noteworthy that edrophonium and tacrine attach only to the anionic site of the enzyme, while organophosphates attach only to the ecstatic site. Reactivation of edrophonium and tacrine inhibited enzyme does not involve hydrolysis of the inhibitor, but only its diffusion—action is brief. The half-life of reactivation of carbamylated enzyme (about 30 min) is less than that of synthesis of fresh enzyme protein, while that of phosphorylated enzyme is more than the regeneration time. The phosphorylated enzyme may also undergo ‘aging’ by the loss of one of the alkyl groups and become totally resistant to hydrolysis. Thus, apparently reversible and irreversible enzyme inhibition is obtained, though the basic pattern of inhibitor-enzyme interaction remains the same.

PHARMACOLOGICAL ACTIONS

• The actions of anti-ChEs are qualitatively similar to that of directly acting echolocator stimulants. However, relative intensity of action on muscarinic, ganglionic, skeletal muscle and CNS sites varies among the different agents.

• Lipid-soluble agents (physostigmine and organophosphates) have more marked muscarinic and CNS effects; stimulate ganglia but action on skeletal muscles is less prominent.

• Lipid-insoluble agents (neostigmine and other quaternary ammonium compounds) produce more marked effect on the skeletal muscles (direct action on muscle endplate echolocators as well), stimulate ganglia, but muscarinic effects are less prominent. They do not penetrate CNS and have no central effects.

• Ganglia Local hydrolysis of Ach is less important in ganglia: inactivation occurs partly by diffusion and hydrolysis in plasma. Anti-ChEs stimulate ganglia primarily through muscarinic receptors present there. High doses cause persistent depolarization of the ganglionic nicotinic receptors and blockade of transmission.

• CVS Cardiovascular effects are complex. Whereas muscarinic action would produce bradycardia and hypotension, ganglionic stimulation would tend to increase heart rate and BP. Action on medullary centers (stimulation followed by depression) further complicates the picture, so does ganglionic blockade with high doses. Thus, the overall effects are often unpredictable and depend on the agent and its dose.

• Skeletal muscles After treatment with attaches, the Ach released by a single nerve impulse is not immediately destroyed rebinds to the same receptor, diffuses to act on neighboring receptors and activates prejunctional fibers → repetitive firing → twitching and fasciculations. Force of contraction in partially curarized and myasthenic muscles is increased. Higher doses cause persistent depolarization of endplates resulting in blockade of neuromuscular transmission → weakness and paralysis. Direct action of neostigmine and its congeners at the muscle endplates results in augmentation of these features 

• Other effects These result from stimulation of smooth muscles and glands of the gastrointestinal, respiratory, urinary tracts and in the eye.

PHARMACOKINETICS

• Physostigmine It is rapidly absorbed from g.i.t. and parenteral sites. Applied to the eye, it penetrates cornea freely. It crosses blood-brain barrier and is disposed after hydrolysis by ChE.

• Neostigmine and congeners These are poorly absorbed orally; oral dose is 20–30 times higher than parenteral dose. They do not effectively penetrate cornea or cross blood-brain barrier. They are partially hydrolyzed and partially excreted unchanged in urine.

• Organophosphates These are absorbed from all sites including intact skin and lungs. They are hydrolyzed as well as oxidized in the body and little is excreted unchanged.

INDIVIDUAL COMPOUNDS

Physostigmine eye drops are usually prepared freshly by ophthalmology departments.

Neostigmine PROSTIGMIN, MYOSTIGMIN, TILSTIGMIN 15 mg tab, 0.5 mg/ml in 1 ml and 5 m

Pyridostigmine Resembles neostigmine in all respects but is dose to dose less potent and longer acting, less frequent dosing is required in myasthenia gravis.

DISTINON, MYESTIN 60 mg tab; 1–3-tab TDS.

Ambe onium is another long-acting congener used in myasthenia.

• Edrophonium Resembles neostigmine in action, has a brief duration (10–30 min), suitable as a diagnostic agent for myasthenia gravis and for postoperative secularization. Dose: 1–10 mg i.v

• Tacrine It is a lipophilic acridine compound which interacts with ChE in a manner analogous to edrophonium. It crosses blood-brain barrier and has a longer duration of action. By increasing brain Ach levels, it has been found to produce partial symptomatic improvement in Alzheimer’s disease (AD) see Ch. 35

• Rivastigmine This lipophilic relatively Cerebro selective ChE inhibitor has been introduced for AD 

• Donepezil Another centrally acting anti-Ache that has produced cognitive and behavioral improvement in AD. It is long-acting and suitable for once daily administration

• Galantamine This natural alkaloid inhibitor of cerebral Ache has in addition weak agonistic action on nicotinic receptors. It is being used to afford symptomatic relief in AD

• Duflo's It is Di isopropyl-fluor-phosphate (DFP), a very potent and long-acting anti-ChE. It has been used as a miotic (0.025%) but is not preferred because it has to be used as oily solution, causes local irritation.

• Echothiopate It is an organophosphate with quaternary structure. It is water soluble; local irritancy is low. A 0.025– 0.25% solution is rarely used in resistant cases of glaucoma as it is a potent and long-acting (1–3 days) miotic

• Precautions Anti-ChEs are contraindicated in sick sinus, A-V conduction defects and hypotensive states. They are to be used cautiously in peptic ulcer, asthma, COPD and seizure patients.

USES

As miotic

• In glaucoma: Miotics increase the tone of ciliary muscle (attached to scleral spur) and sphincter pupillae which pull on and somehow improve alignment of the trabeculae so that outflow facility is increased → i.o.t. falls in open angle glaucoma.

• Pilocarpine is the preferred miotic. The action is rapid and short lasting (4–6 hr); 6–8 hourly instillation is required and even then i.o.t. may fluctuate in-between. Diminution of vision, especially in dim light (due to constricted pupil), spasm of accommodation and brow pain are frequent side effects. Systemic effects—nausea, diarrhea, sweating and bronchospasm may occur with higher concentration eye drops

• Physostigmine (0.1%) is used only to supplement pilocarpine. Miotics are now 3rd choice drugs, used only as add on therapy in advanced cases. However, they are effective in aphakic glaucoma. Pilocarpine (along with other drugs) is used in angle closure glaucoma as well.

• To reverse the effect of mydriatics after refraction testing.

• To prevent formation of adhesions between iris and lens or iris and cornea, and even to break those which have formed due to iritis, corneal ulcer, etc.—a miotic is alternated with a mydriatic.

Myasthenia gravis

• Myasthenia gravis is an autoimmune disorder affecting about 1 in 10,000 population, due to development of antibodies directed to nicotinic receptors (NR) at the muscle endplate → reduction in number of free NM echolocators to 1/3 of normal or less (Fig. 7.3) and structural damage to the neuromuscular junction → weakness and easy fatigability on repeated activity, with recovery after rest. Neostigmine and its congeners improve muscle contraction by allowing Ach released from prejunctional endings to accumulate and act on receptors over a larger area, and by directly depolarizing the endplate.

• Treatment is usually started with neostigmine 15 mg orally 6 hourlies; dose and frequency is then adjusted according to response. However, the dosage requirement may fluctuate from time to time and there are often unpredictable periods of remission and exacerbation. Pyridostigmine is an alternative which needs less frequent dosing. If intolerable muscarinic side effects are produced, atropine can be added to block them. These drugs have no effect on the basic disorder which often progresses; ultimately it may not be possible to restore muscle strength adequately with attaches alone.

• Corticosteroids afford considerable improvement in such cases by their immunosuppressant action. They inhibit production of NR-antibodies and may increase synthesis of NRs. However, their long-term use has problems of its own (see Ch. 20). Prednisolone 30–60 mg/day induces remission in about 80% of the advanced cases; 10 mg daily or on alternate days can be used for maintenance therapy. Other immunosuppressants have also been used with benefit in advanced cases. Both azathioprine and cyclosporine also inhibit NR-antibody synthesis by affecting T-cells, but response to the former is slow in onset (takes upto 1 year), while that to the latter is relatively quick (in 1–2 months). Removal of antibodies by plasmapheresis (plasma exchange) is another therapeutic approach. Dramatic but short-lived improvement can often be achieved by it in myasthenic crisis.

• Myasthenic crisis is characterized by acute weakness of respiratory muscles. It is managed by tracheal intubation and mechanical ventilation. Generally, i.e. methylprednisolone pulse therapy is given while anti-ChEs are withheld for 2–3 days followed by their gradual reintroduction. Most patients can be weaned off the ventilator in 1–3 weeks. Plasmapheresis hastens recovery.

• Overtreatment with anti-ChEs also produces weakness by causing persistent depolarization of muscle endplate: this is called cholinergic weakness. Late cases with high anti-ChE dose requirements often alternately experience myasthenic and cholinergic weakness and these may assume crisis proportions

• Postoperative paralytic ileus/urinary retentions This can be relieved by 0.5–1 mg sic neostigmine, provided no organic obstruction is prese

• Postoperative secularization Neostigmine 0.5–2.0 mg i.e., preceded by atropine to block muscarinic effects, rapidly reverses muscle paralysis induced by competitive neuromuscular blockers.

• Cobra bite Cobra venom has a curare like neurotoxin. Though specific antivenom serum is the primary treatment, neostigmine + atropine prevent respiratory paralysis.

• Belladonna poisoning Physostigmine 0.5–2 mg i.e., repeated as required is the specific antidote for poisoning with belladonna or other anticholinergics. It penetrates blood-brain barrier and antagonizes both central and peripheral actions. However, physostigmine often itself induces hypotension and arrhythmias; is employed only as a last resort. Neostigmine does not block the central effect but is less risky.

• Other drug overdosages Tricyclic antidepressants, phenothiazines and many antihistaminic have additional anticholinergic property. Overdose symptoms and coma produced by these drugs are partly antagonized by physostigmine. It also appears to have a modest nonspecific arousal effect in CNS depression produced by diazepam or general an aesthetics but is rarely used.

• Alzheimer’s disease Characterized by progressive dementia, is neurodegenerative

• disorder, primarily affecting cholinergic neurons in the brain. Various measures to augment cholinergic transmission in the brain have been tried. The relatively Cerebro selective anti-ChEs tacrine, rivastigmine, donepezil and galantamine have been approved for clinical use. For details see

ANTICHOLINESTERASE POISONING

Anticholinesterases are easily available and extensively used as agricultural and household insecticides; accidental as well as suicidal and homicidal poisoning is common.

Local muscarinic manifestations at the site of exposure (skin, eye, g.i.t.) occur immediately and are followed by complex systemic effects due to muscarinic, nicotinic and central actions. They are—

• Irritation of eye, lacrimation, salivation, sweating, copious trachea-bronchial secretions, miosis, blurring of vision, breathlessness, colic, involuntary defecation and urination. 

• Fall in BP, bradycardia or tachycardia, cardiac arrhythmias, vascular collapse. 

• Muscular fasciculations, weakness, respiratory paralysis (central as well as peripheral). 

• Excitement, tremor, ataxia, convulsions, coma and death. 

• Death is generally due to respiratory failure.

Treatment

• Termination of further exposure to the poison—fresh air, wash the skin and mucous membranes with soap and water, gastric lavage according to need. 

• Maintain patent airway, positive pressure respiration if it is failing. 

• Supportive measures—maintain BP, hydration, control of convulsions with judicious use of diazepam. 

Specific antidotes—

• Atropine It is highly effective in counteracting the muscarinic symptoms, but higher doses are required to antagonize the central effects. It does not reverse peripheral muscular paralysis which is a nicotinic action. All cases of anti-ChE (carbamate or organophosphate) poisoning must be promptly given atropine 2 mg i.e. repeated every 10 min till dryness of mouth or other signs of utopianization appear (up to 200 mg has been administered in a day). Continued treatment with maintenance doses may be required for 1–2 weeks.

• Cholinesterase reactivators Oximes are used to restore neuromuscular transmission in case of organophosphate anti-ChE poisoning. The phosphorylated ChE reacts very slowly or not at all with water. However, if more reactive OH groups in the form of oximes (generic formula R–CH = N–OH) are provided, reactivation occurs more than a million times faster (see Fig. 7.2G and H). 

Chronic organophosphate poisoning Repeated exposure to certain fluorine containing and triaryl organophosphates results in polyneuritis and demyelination after a latent period of days and weeks. Sensory disturbances occur first followed by muscle weakness, tenderness and depressed tendon reflexes— lower motor neuron paralysis. In the second phase, spasticity and upper motor neuron paralysis gradually supervenes. Recovery may take years. The mechanism of this toxicity is not known, but it is not due to inhibition of ChE; there is no specific treatment.