AUTONOMIC NERVOUS SYSTEM-PART-IV

NEUROMUSCULAR BLOCKING AGENTS

These drugs block completely the neuromuscular cholinergic transmission by blocking at the nicotinic receptors of the somatic system. The somatic nervous system (SNS) is as we have already seen as a part of the Peripheral Nervous System(PNS) apart from ANS. Even though it is to some extent limits to a voluntary nervous system but beyond the limits, it may become autonomous.

The drugs which block the cholinergic transmissions at the neuromuscular junction causes muscle relaxation and are used as adjuvant drugs to produce anesthesia.

Classifications:-

1.Nondepolarizing blockers

2.Depolarizing blockers

A.Nondepolarizing blockers:-

1.Tubocurarine

2.Pancuronium 

3.Atracurium

4.Vecuronium

Among them, pancuronium has a longer duration of action.

They are not affecting all the muscles together but in order of first, the eye muscles followed by the facial muscles and at last the respiratory muscles.

Because of the poor intestinal absorption, these medicines are recommended by intravenous routes.

Side effects

They produce severe allergic reactions as they stimulate histamine release causes severe anaphylactic reactions, shock, hypotension, tachycardia followed by respiratory failure.

The above side effects can be effectively counteracted by administering a cholinergic agonist such as edrophonium, or neostigmine.

B.Depolarizing Blockers:-

Membrane depolarization usually occurs by the action of acetylcholine at its nicotinic receptors and the sodium channels are opened and rapid exchange of positively charged sodium ions from outside to inside the neuronal axon(lumen) through its channels to depolarize the muscle and when the threshold reached the acetylcholine is rapidly inactivated by the acetylcholinesterase and action potential occur followed by the rapid repolarization to sensitize our muscle for its normal functioning.

The depolarizing blockers such as Succinylecholine(Suxamethonium) is acting in a similar manner to acetylcholine by binding to the nicotinic receptor and causes depolarization. But as succinylcholine is not inactivated by the enzyme the depolarization is prolonged and goes beyond the threshold and the receptor is continuously desensitized to acetylcholine so that there is no or very weak action potential occur and the muscle is relaxed or paralyzed.

The duration of action is very short (3 to 6 min)

Unlike acetylcholine which is metabolized by the enzyme acetylcholinesterase, succinylcholine is metabolized by plasma cholinesterase.

It is used as an adjuvant in general anesthesia.

Since the neuromuscular blockers have effect only on nicotinic Nm subtype receptors and hence they have no ganglionic blocking effect at Nn subtype.

 

 

 

AUTONOMIC NERVOUS SYSTEM-PART-III

NEUROMUSCULAR BLOCKING AGENTS

These drugs block completely the neuromuscular cholinergic transmission by blocking at the nicotinic receptors of the somatic system. The somatic nervous system (SNS) is as we have already seen as a part of the Peripheral Nervous System(PNS) apart from ANS. Even though it is to some extent limits to a voluntary nervous system but beyond the limits, it may become autonomous.

The drugs which block the cholinergic transmissions at the neuromuscular junction causes muscle relaxation and are used as adjuvant drugs to produce anesthesia.

Classifications:-

1.Nondepolarizing blockers

2.Depolarizing blockers

A.Nondepolarizing blockers:-

1.Tubocurarine

2.Pancuronium 

3.Atracurium

4.Vecuronium

Among them, pancuronium has a longer duration of action.

They are not affecting all the muscles together but in order of first, the eye muscles followed by the facial muscles and at last the respiratory muscles.

Because of the poor intestinal absorption, these medicines are recommended by intravenous routes.

Side effects

They produce severe allergic reactions as they stimulate histamine release causes severe anaphylactic reactions, shock, hypotension, tachycardia followed by respiratory failure.

The above side effects can be effectively counteracted by administering a cholinergic agonist such as edrophonium, or neostigmine.

B.Depolarizing Blockers:-

Membrane depolarization usually occurs by the action of acetylcholine at its nicotinic receptors and the sodium channels are opened and rapid exchange of positively charged sodium ions from outside to inside the neuronal axon(lumen) through its channels to depolarize the muscle and when the threshold reached the acetylcholine is rapidly inactivated by the acetylcholinesterase and action potential occur followed by the rapid repolarization to sensitize our muscle for its normal functioning.

The depolarizing blockers such as Succinylecholine(Suxamethonium) is acting in a similar manner to acetylcholine by binding to the nicotinic receptor and causes depolarization. But as succinylcholine is not inactivated by the enzyme the depolarization is prolonged and goes beyond the threshold and the receptor is continuously desensitized to acetylcholine so that there is no or very weak action potential occur and the muscle is relaxed or paralyzed.

The duration of action is very short (3 to 6 min)

Unlike acetylcholine which is metabolized by the enzyme acetylcholinesterase, succinylcholine is metabolized by plasma cholinesterase.

It is used as an adjuvant in general anesthesia.

Since the neuromuscular blockers have effect only on nicotinic Nm subtype receptors and hence they have no ganglionic blocking effect at Nn subtype.

 

 

 

AUTONOMIC NERVOUS SYSTEM-PART-II-CONTINUED

INDIRECTLY ACTING CHOLINERGIC STIMULANTS(AGONISTS)

These are the drugs enhancing cholinergic activities indirectly by inhibiting the enzyme acetylcholinesterase (which is responsible for hydrolyzing and inactivating acetylcholine) and thereby enhancing the acetylcholine activities.

There are two types of enzyme inhibitors as follows:-

A.IRREVERSIBLE INHIBITORS(PESTICIDE POISONING)

The followings are a few examples:-

1.Isoflurophate

2.Echothiophate

3.Parathion

All the above examples belong to a chemical group of organophosphates the pesticide poisons. Most of the pesticides contain organophosphates and are used for suicidal self-poisoning or careless accidental poisoning. In the olden days, these compounds are used in wars as nerve gases.

Organophosphates are very powerful and cause serious side effects as they irreversibly inactivate the enzyme acetylcholinesterase by forming covalent bonds. This will cause prolonged and overactivity of acetylcholine causes serious cholinergic crisis such as

1.Respiratory depression(Bronchoconstriction and increased secretions)

2.Bradycardia(depressed heart rate)

3.Diarrhea

4.Enuresis(Involuntary urination)

5.Over sweating

6.Blurred vision(Miosis)

and all the already elucidated DUMBELS cholinergic crisis leads to death.

These covalent bonds are mostly irreversible yet if a cholinesterase reactivator such as pralidoxime is given immediately along with a muscarinic antagonist like atropine in order to avoid phosphorylation of the enzyme irreversibly. Pralidoxime act immediately at bonding reaction between the active site of the enzyme and the phosphate radical of the drug. This action prevents the aging of the bond to become irreversible and the phosphate radical would easily be removed from the enzyme which becomes active again.

Treatments of organophosphates pesticide poisoning need immediate hospitalization with blood samples for assays to estimate the level of inactivation of the enzyme. The loss of fluids and electrolytes due to diarrhea should be compensated. Respiration should be monitored and corrected by giving appropriate respiratory stimulants.

Atropine should be given according to the doctor's advice along with the enzyme reactivators.

Uses

Very rarely these compounds are used in glaucoma, accommodative esotropia (Crossed Eye) 

B.REVERSIBLE INHIBITORS

1.Edrophonium (short-acting)

2.Physostigmine

3.Neostigmine

4.Pyridostigmine

All the above are natural and synthetic alkaloids. Physostigmine occurs naturally in Calabar beans(Physostigma venenosum)

Unlike organophosphates, these compounds have not inactivated the enzyme irreversibly. They do not form covalent bonds with the enzyme. Hence they have some therapeutic values.

A.Physostigmine

1.Second choice of drug in glaucoma after pilocarpine

2.Used to counteract an overdose of atropine, phenothiazines, and tricyclic antidepressants.

3.Used in intestinal atony.

Side effects:-

Physostigmine can cross CNS as it is a tertiary amine(unionized), can cause convulsions. Other effects are similar to DUMBELS

B.Neostigmine

Neostigmine is a synthetic alkaloid similar to physostigmine but it will not enter into CNS by crossing the blood-brain barrier as it is a quaternary carbamate compound forms highly polarized hydrophilic positive quaternary ammonium ion.

Use

1. This is the drug of choice in the treatment of myasthenia gravis the neuromuscular disease in which muscle weakness and fatigue manifest.

2.Treating urinary retention 

3.Treating paralysis of the small intestine(paralytic ileus)

4.The antidote for tubocurarine poisoning.

Neostigmine is acting a short course of action when compared with physostigmine usually of  2 to 4 hours

Side effects:-

DUMBELS

C.Edrophonium 

Edrophonium is similar to neostigmine and its a course of action is very shorter than neostigmine such as 5 to 15 minutes.

Because of this edrophonium is not used in maintenance therapy but can be as a diagnostic agent to differentiate myasthenia gravis from the cholinergic crisis. Both conditions can bring muscle weakness but administration of edrophonium may improve myasthenia gravis but worsens the cholinergic crisis.

Side effects:-

DUMBELS

C.Pyridostigmine    

Its duration of action is 3 to 6 hours.

Used conveniently in myasthenia gravis

Side effects:-

DUMBELS 

 

 

 

 

 

AUTONOMIC NERVOUS SYSTEM-PART-II

CHOLINERGIC STIMULATION

In the ANS acetylcholine is the major autonomic nerve transmitter in all the preganglionic fibers and the parasympathetic postganglionic fibers and the sympathetic postganglionic fibers supplied to the sweat glands.

Acetylcholine is acting on the nicotinic receptors in the preganglionic level of both sympathetic and parasympathetic systems, and muscarinic receptors at the postganglionic level.

This can be detailed as follows:-

1.Preganglionic fibers of autonomic ganglia (Nn)

2.Preganglionic fibers that supplied to the adrenal medulla (Nn)

3.Postganglionic fibers of the parasympathetic system (M)

4.Postganglionic fibers of the sympathetic system that supplied to the sweat glands(M)

Nn means the nicotinic receptor at the neuronal level the name earned because it was first identified by nicotine.

M means the muscarinic receptor because it was first identified by using muscarine.

Here we deal with drugs that mimic acetylcholine's cholinergic stimulant actions.

These drugs are known as cholinomimetics and are categorized as follows:-

1.Direct Acting Stimulants (Agonists)

These are acting by chemically binding with the acetylcholine's nicotinic and muscarinic receptors in the body.

a.Acetylcholine

This is the natural endogenous prototype drug secreted within our body and affects almost every system in our body. This can be summarised as follows:-

Cardiovascular system In this system if acetylcholine dominates by acting on its muscarinic receptors in the parasympathetic postganglionic level as in rest and sleep, it decreases heart rate, B.P., and contractility.

Digestive system Increases intestinal motility

Urinary system Increases contractility of the bladder 

Pulmonary system It increases pulmonary secretions.

The eye In the eyes it causes pupillary constriction (miosis) 

Periphery It causes contraction of the muscles by its somatic nicotinic receptors(Nm) at the neuromuscular junction

Endocrine system It causes the release of adrenaline from the adrenal medulla by its nicotinic action.

As a medicine, this drug is very rarely used to produce miosis in the eyes and its use is very limited as it has widespread unwanted actions and is rapidly destroyed by acetylcholinesterase and eliminated by the body.

Side effects

Diarrhea and Decreased BP

Urination

Miosis

Bronchial secretions and Bradycardia

Excitation of the bone muscles

Lacrimation

Salivation

The side effects can be easily memorized by the anagram 'DUMBELS'

b.Bethanechol 

It is chemically a carbamic acid ester.

It acts mainly on muscarinic receptors

Therapeutically it can be used to relieve constipation and urinary retention.

Side effects

Similar to that of acetylcholine

c.Carbachol

It is also similar to bethanechol a carbamic ester but because of more side effects due to nicotinic effects the drug is very rarely used to produce miosis during eye surgery and in glaucoma

Acting on both muscarinic and nicotinic receptors

Side effects similar to that of acetylcholine

d.Pilocarpine

Pilocarpine is an alkaloid from the leaves of typical south American shrubs from the genus Piocarpus

Causes,

miosis

decreased heart rate

bronchial contractions

increase salivary, lacrimal and sweat secretions

The drug is unaffected by the enzyme acetylcholinesterase and hence yield prolonged action.

This is the drug of choice for the treatment of glaucoma

It has the advantage of acting primarily on muscarinic receptors only.

Side effects

Similar to acetylcholine but in addition to that it can enter the CNS to give effects like migraine,delusions, dizziness, etc.

e.Methacholine

Because of its short duration of action, it can be used for diagnosing asthma and bronchial hyperactivity.

Acting mainly on muscarinic receptors.

Side effects are due to generalized cholinergic stimulation.

-Continued (Indirect Acting Agonists)next post. 

 

 

AUTONOMIC NERVOUS SYSTEM-PART-1

AUTONOMIC NERVOUS SYSTEM(ANS)-OVER VIEW

In general, our nervous system is divided into two branches such as 1.Central Nervous System(CNS) which is centered at the brain systems and highly protected by the blood-brain barrier and skull.

2. Peripheral Nervous System(PNS) which is centered outside the brain midbrain, and spinal cord and is not much protected as CNS. Hence PNS is highly prone to be injured by toxins and mechanical means.

PNS is acting as a mediator between the end organs with the CNS.

The PNS  is again divided into two such as 1. The Somatic nervous system supplied to the skeletal muscles to express our voluntary desired movements to the brain by sending and receiving back and forth the impulses and commands from the brain accordingly.

2. Autonomous Nervous System is an involuntary control of smooth muscles such as the heart, lungs, and liver etc.etc.

The system is connected to the CNS in two different physiological networks known as the sympathetic and parasympathetic nervous systems.

The autonomic nervous system is defined as a collection of nuclei, cell bodies, nerves ganglia, and plexuses that provides afferent and efferent nerves supplied to the smooth muscles and visceral organs that carries commands from the brain and stimuli or impulses to the brain by the end involuntary smooth muscles and organs.75% of the ANS nerve networks are linked with the CNS through the medulla oblongata.

 The autonomic nervous system is so important as it regulates involuntary functions such as blood pressure, heart rate, and the digestive system.
As in the diagram above the ANS is divided anatomically into two major components as follows:-
1.Parasympathetic Nervous System in which there is a long preganglionic fiber that snaps with a short postganglionic fiber at the ganglion situated somewhere nearby the target organ as in the diagram shown above. The preganglionic fibers originate from cranial nerve nuclei III, VII, IX, and X as well as the III and IV sacral spinal roots and this system is known as craniosacral outflow
2.Sympathetic Nervous System in which there are short preganglionic fibers that snap with the long postganglionic fibers at the ganglia to form a sympathetic ganglionic chain adjacent to the spinal cord. All preganglionic fibers of the sympathetic nervous system originate in the thoracolumbar portion of the spinal cord and it is known as thoracolumbar outflow
Pharmacologically acetylcholine is the nerve transmitter in the preganglionic fibers of both the systems and postganglionic fibers of the parasympathetic nervous system.

Norepinephrine is the major nerve transmitter at the postganglionic nerves in the sympathetic nervous system except the postganglionic sympathetic nerve supply in which acetylcholine is the nerve transmitter. 
Responses of the effector organs to the autonomic nervous system can give us an outline of predicting various drugs that mimic or antagonize the actions of these nerves.
The two divisions of the ANS are generally antagonizing each other in some sites like the heart and digestive system and synergizing in some sites such as in sex organs.

General Functions Of ANS

Generally, the combined functions of the ANS are important in regulating the activities of vital organs which are functioning involuntarily below the level of consciousness. Thus respiration, circulation, digestion, body temperature, metabolism, sweating, and endocrine secretions of hormones are all regulated and controlled in part or entirely by ANS.

Specific Functions Of ANS

The specific functions of the two divisions of the ANS can be emphasized as follows:-

1. The sympathetic nervous system is the predominant one in normal situations as the majority of the combined nerve supply to various parts of our body belongs to this anatomical division of ANS. This nervous system is active even at rest but becomes dominant during stress by its adrenergic postganglionic activity. For example, if you feel danger or angry, or any other mind provoking thoughts, your heart rate increases, blood pressure rises, eyes dilate, blood sugar rises, lungs expand with more oxygen demand, and the face and parts of the body reddened as the blood flow shifts from the skin to skeletal muscle in order to get ready for a fight or flight.

The effector organs are responding to sympathetic(adrenergic) stimulations by the following receptors such as alpha-1,alpha-2;

beta-1,beta-2;and dopamine receptors.

In contrast, the parasympathetic nervous system which is not much innervated in our body is predominant at rest, sleep, and the situation of calmness. It is a nervous system of peace and tranquil. Stimulation of this nervous system in which the postganglionic fibers are 100% cholinergic slows heart rate, lower blood pressure, increase intestinal motility, constrict the pupil(miotic) and empty the urinary bladder. In general, this is a peace and digestive system.

The effector organs respond to this system(Cholinergic) at the receptors such as nicotinic(Nm, Nn) and muscarinic(m-1 to m-5)

The two systems are working and active all the time. Their action is antagonized to each other according to the situations. For example, the heart rate is normally under the influence of cholinergic. But when the situation gets tense the heart rate goes under the influence of the adrenergic sympathetic nervous system.

Nerve Transmitters

Apart from the anatomical sympathetic division of ANS, a pharmacological division of ANS is more convenient to understand their activities by means of the autonomical transmitters as follows:-

1.Cholinergic Nervous System in which the transmitter at the target organ is Acetylcholine

2.Adrenergic Nervous System in which the transmitter at the target organ is Norepinephrine.

The calcium ion is required to release the transmitters from their storage vesicles. 

  

NERVE DEGENERATIVE DISORDERS -PART-IV

HUNTINGTON'S DISORDER(HD)

HD is a dominantly inherited disorder characterized by the gradual onset of mobility disorders followed by mental insufficiency. The condition is very common at a young age to mid-age.

Symptoms start insidiously either as a mobility disorder or a cognitive and personality disorder or both. The movement disorders consist of a brief jerk like movements of the extremities, trunk, face, and neck(chorea).

Motor incoordination and impairment of rapid eye movements are the early symptoms. If the onset of the disease occurs in the early 20s the choreic movements are less prominent but instead, bradykinesia(slow neuromuscular response) and dystonia (involuntary contract movement of muscles) are the prominent features.

As the disease progresses the dystonic muscle movements are more frequent and severe, leads to dysarthria(Arthritis like pain and speech difficulty), followed by dysphagia(pain and difficulty in swallowing), and balance to stand or walk is impaired.

Cognitive disorder slowly onset by slow mental processing and difficulty in organizing complex tasks.

Memory in distance and long ago may be impaired but short memories and memory of family friends, close relatives, and immediate incidences may be spared. Hence such persons always seem to be irritant anxious and depressed.

Less frequently paranoia and delusions may manifest.

Over a course of 20 to 30 years, the affected person becomes totally disabled and unable to communicate and require full-time care.

Death ensues from the complications of immobility.

Neurology

In general similar to the other neurological disorders, the HD also caused by the neuronal degeneration at the forebrain in which the reward system is present. The damages are mainly at the nerve nucleus known as caudate nucleus along with the round-shaped nerve capsule known as putamen composed parts of the basal ganglia, at the forebrain.HD is purely a genetic disorder due to a single defect on chromosome-4.

Treatments

There is no cure for the disease but medicines are used in a limited sense because of the side effects to control the symptoms.

1. Depression can be treated with antidepressant drugs such as tricyclic antidepressants(Amitriptyline, imipramine) but their anticholinergic effects which may exacerbate chorea. should be excluded.

SSRIs such as Fluoxetine can be employed to treat depression and irritability with a safe profile.

Antiepileptics such as Carbamazepine has also been tried successfully to relieve depression.

Neuroleptics such as clozapine and risperidone can be used but the doses should be lower than their dose employed in psychiatric disorders. At high doses, they may impair cognitive functions and mobility.

For those with large amplitude chorea causing frequent falls and injury can try antidopaminergic drugs such as haloperidol or tetrabenazine or reserpine. During the dopamine depleting drugs treatment patient should be watched for depression and hypotension.

Benzodiazepines like alprazolam, diazepam, or temazepam can be used to relieve anxiety and stress.
Seizures can be controlled by anticonvulsants such as clonazepam or valproic acid

NERVE DEGENERATIVE DISORDERS-PART-III

ALZHEIMER'S DISEASE

Alzheimer's Disease is a cognitive and memory disorder that usually occurs at the age of 60 and above. The onset of the disease is slow but with a definite progression. It may take 10 to 15 years to attain the fully developed stage at which the patient lost short and distant memories, inability to recognize anything, and become immobile with physical sufferings by infections. Death usually resulted in the cause of pneumonia or pulmonary embolism.

Pathophysiology 

The major pathophysiology is the atrophy and damages of the cerebral cortex and subcortical neurons. Unlike PD, in AD, there are no much damages at the midbrain and hence there are no postural and extrapyramidal irregularities.

In the process of aging, there is a synthesis of neurons are progressed at the cerebral cortex usually in the grey matter. During the process, by-products are formed as plaques and deposited at the grey matter.

These deposits are larger in number and are mainly made of beta-amyloid. These plaques are neurotoxic and cause further degenerations of neurons in the cortex results in Alzheimer's Disease(AD). 

Although small numbers of senile plaques and neurofibrillary tangles are common in normal individuals they are far more abundant in AD and the abundance is directly proportional to the cognitive impairment.

Unlike Parkinson's Disease in which the main pathophysiology is the loss of dopaminergic neurons in the midbrain but in Alzheimer's Disease, there is a major loss of cholinergic neurons with a hefty insufficiency of acetylcholine input at the cerebral cortex particularly at the basal forebrain that provide cholinergic innervation to the whole cerebral cortex. Also unlike in PD in AD, there is far more loss of neurotransmitter networks such as serotonin, glutamate, and neuropeptides to make it more complicated.

Treatments

One of the major basics of the treatment of the AD is to restore or normalize the acetylcholine input and to normalize the cholinergic innervation of the cortex. The approach with acetylcholine precursors such as choline chloride and lecithin was found with no expected benefits.

Direct injection of cholinergic agonists such as bethanechol into the intracerebroventricular region yield some benefits. But this is complicated with the need for surgical implantation of a reservoir connecting to the subarachnoid space(the space between the arachnoid mater and the pia mater ).

Later on, there are some more easy and improved methods such as the use of acetylcholinesterase inhibitors such as physostigmine a reversible inhibitor are developed. The use of physostigmine is limited because of its short half-life and side effects like a cholinergic crisis in therapeutic doses.

Recently the American FDA has approved a drug known as tacrine an acridine derivative for the treatment of AD. It is a potent centrally acting inhibitor of the enzyme AchEsterase.An I.V.injection of tacrine is tried with major flaws

Laer on oral tacrine combined with lecithin is tried successfully.

Side effects of oral tacrine

1.Abdominal cramp

2.Nausea and vomiting

3.Diarrhea

4.Liver toxicity(elevation of serum transaminases)

but liver enzymes rapidly subsided by withdrawing the medicine.