AUTONOMIC NERVOUS SYSTEM-PART-VI-Continued...

DIREC ACTING BETA SELECTIVE AGONISTS

These drugs are stimulating selectively at beta receptors of the postganglionic adrenergic nervous system.

Beta-1 receptors are mostly situated on the postsynaptic membrane and beta-2 receptors are found both in pre and postsynaptic membrane.

Beta receptors are present in heart muscle and their stimulation may cause an increase in heartbeat, rate, and rhythm by an increase in both inotropic and chronotropic effects.

Beta-1stimulation leads to increased lipolysis.

Beta-2 receptor stimulation works through adenylate cyclase to dilate the vasculature in bronchial as well as skeletal muscles.

The uterus, ciliary and detrusor muscles are relaxed.

Glucagon release is increased.

Both b-1 and b-2 receptor stimulation leads to reduced intestinal tone and motility.

1.Dobutamine

It is a dopamine derivative

Primarily act on the beta-1 receptor with a secondary effect on beta-2 receptor

The physiological effects of dobutamine are increased heart rate, and contractility(beta-1);

Smooth muscle relaxation (beta-2)

Use

Treatment of unstable CHF and shock.

Route

Intra venously

Side effects

1.Arrhythmias

2.Hypertension

3.Headaches

4.Palpitations

5.Angina

6.Nausea.

2.Isoproterenol

It acts equally on both b-1 and b-2.

Physiological effects

1.Increases both cardiac inotropic and chronotropic effects(b-1)

2.Increases peripheral vascular resistance(b-2)

3.Relaxes smooth muscles(b-2)

Use

It is appropriate to use isoproterenol in 

1.Stimulate heart rate in heart block and bradycardia

2. To treat asthma but now it becomes older.

I.V route is preferable

Side effects

1.Arrhythmias

2.Palpitation

3.Tachycardia

4.Headache

3.Albuterol, Metaproterenol, and Terbutaline

Mainly on b-2 receptors causes smooth muscle relaxations

But on concentration may affect b-1

Albuterol and metaproterenol can be given by inhalation

Terbutaline by oral or s.c

Uses

1.Asthma

2.Chronic Obstructive Pulmonary Disease

3.Bronchitis

4.Uterine relaxation in premature labour-Terbutaline and ritodrine

Side effects

Similar to the above 

AUTONOMIC NERVOUS SYSTEM-PART-VI

ADRENERGIC AGONISTS

Those drugs similar to endogenous catecholamines acting on the adrenergic postganglionic receptors and stimulate them are known as Adrenergic Stimulants or Adrenergic Agonists. Since anatomically most of the sympathetic postganglionic major nerve transmitter is noradrenaline except a few it is also known as Sympathetic Stimulants or Sympathomimetics.

They can be classified as direct or indirect as well as receptors specified such as a1,a2,b1,b2.

A comprehensive classification is as follows:-

1.Peripheral excitatory action on certain smooth muscles such as blood vessels of the skin, kidney, mucous membranes, salivary, and sweat glands.

2.Peripheral inhibitory actions on certain other types of smooth muscles such as an intestinal wall, bronchial tree, and in blood vessels of skeletal muscles.

3.Cardiac excitatory actions

4.Metabolic actions

5.Endocrine actions

6.CNS actions

7.Presynaptic actions.

Chemistry of noradrenaline

Norepinephrine or noradrenaline is an isomer of adrenaline in which the methyl radical is replaced by a hydrogen ion as seen in the following structure. The basic structure of all sympathomimetic drugs is based on the structure of the compound phenylethylamine. A phenyl radical (a benzene ring attached with a phenolic hydroxyl group) attached with an ethylamine side chain.

Noradrenaline as seen in the above structure is demethylated adrenaline (nor means demethyl). It is more potent than adrenaline and highly unstable. All these compounds are derivatives of catecholamines or hydroxy phenylethylamines

Physiological Functions of Adrenergic Receptors

To a comprehensive study of how different adrenergic agonists differing in their action at the specific target tissues the following details will elucidate that.

The different adrenergic receptors are present in different concentration at different sites as follows:

1. Bronchial smooth muscles are largely concentrated with b-2 receptors and hence only beta-2 agonists like isoproterenol and ephedrine have to influence on these muscles

2. Cutaneous blood vessels are concentrated with receptors and hence alpha agonists like adrenaline, noradrenaline has an influence on these muscles.

3. The blood vessels supplied to skeletal muscles are concentrated with both alpha and beta-2 receptors and hence both agonists have an influence on these muscles accordingly, such as stimulation of beta-2 receptor causes vasodilation whereas stimulating alpha receptor causes vasoconstriction.

In skeletal muscle, the threshold concentration for activation of beta-2 receptors by epinephrine is lower than the concentration needed to stimulate alpha receptors but at a high concentration of epinephrine, the alpha stimulation predominates.

1.Alpha(a)Selective Direct Acting Agonists

A.Alpha-1 Receptors

i.Phenylephrine

Its primary action is on blood vessel smooth muscle where alpha-1 receptors are present and causes vasoconstrictions and consequently raises blood pressure results in reflex bradycardia

Use-

1.As a nasal decongestant

2. To treat hypotension.  

3.Eye tests(mydriasis)

4. To terminate paroxysmal atrial tachycardia

Side effects

1.Rebound mucosal swelling

2.Hypotensive headache

ii.Methoxamine

Similar to phenylephrine this drug acts specifically on the alpha-1 receptor.

Use

1.Treatment of hypotension

2.Paroxysmal Atrial Tachycardia(PAT)

B.Alpha-2 Receptors

In this category, there are two drugs that act specifically on alpha two receptors.

Remember that stimulating alpha-2 receptors will stop the further secretion of noradrenaline from the presynaptic fiber and hence there is a reduction in the sympathetic outflow

I. Clonidine

Clonidine stimulates the adrenergic alpha-2 receptors of the CNS and thereby causes a reduced sympathetic outflow from the brain.

Uses

1.Treatment of hypotension

2.Withdrawal symptoms of benzodiazepines and opiates

3.Treatment of diarrhea in DM with autonomic neuropathy.

Side effects

1.Sedation

2.Dry mouth

3.Sexual dysfunction

4.Orthostatic hypotension

 

 

 

AUTONOMIC NERVOUS SYSTEM-PART-V-Continued...

Ganglionic Blockers-Continued...

These agents are antagonizing or blocking acetylcholine to act on its neuronal nicotinic (Nn,)receptors at the ganglia.

As we all know the Nn receptor action of acetylcholine is necessary to release the respective transmitters of cholinergic and adrenergic postganglionic end to act on the respective target cells.If these ganglionic Nn receptors are blocked both the systems will be affected not at the same degree but in different degrees in different effector sites as follows:-

Heart-In heart normally parasympathetic (cholinergic) nervous system is prominent to keep the heartbeat in a proper peaceful rhythm. But by blocking the ganglia, the system would lose its prominence and the unopposed sympathetic(adrenergic)system would raise the heart rate leads to tachycardia, and arrhythmias and blood pressure would rise.

Blood vessels-The The arteries and veins are dilated to deliver more blood to the periphery as the predominant sympathetic(adrenergic)system loses its prominence.

Eye-The normally predominant parasympathetic system loses its hold and the unopposed sympathetic system produces cycloplegia and mydriasis (dilation of the pupil)

Digestive system-The The normally predominant parasympathetic nervous system loses its hold leads to unopposed sympathetic effects such as constipation, dry mouth, reduced gastric and pancreatic secretions.

The urinary system-The usual predominant parasympathetic system loses its hold leads to urinary retention 

Sweat glands-The usually predominant sympathetic (cholinergic) effect loses its hold to sweat block(hot flashes)

Classifications of Ganglionic Blockers

1. Depolarizing GBs-These are the agents such as nicotine first stimulating the Nn-receptor in the ganglia and depolarize it similar to acetylcholine. But with persisting prolonged depolarization the action potential is nullified and the receptor is further desensitized to acetylcholine followed by the ganglionic blockade.

That is why in the tobacco(nicotine) poisoning at first the heart rate is increased due to the stimulation of the sympathetic ganglia and adrenal medulla to release more catecholamines followed by the ganglionic blockade to counteract these effects

(e.g.) Nicotine and Labeling

These drugs have no therapeutical values.

2.Non-depolarizing GBs -These drugs directly block the receptors without prior stimulations or depolarizing effects.

(e.g) hexamethonium, mecamylamine, and trimetaphane.

Because of the severe toxicities and complications these drugs used very rarely in treatments.

 

AUTONOMIC NERVOUS SYSTEM-PART-V

GANGLIONIC BOCKING AGENTS

What is a ganglion? A ganglion is a singular form in number for which the plural term is ganglia is a small round shaped nerve node at which two nerve fibers one from the spinal cord towards the ganglion the preganglionic fiber and the other from the ganglion to the target tissues, the postganglionic fiber are snapped together with a small gap between the presynaptic and postsynaptic receptors. The above video may give a proper study of the ganglion. If you want a thorough about ganglia please watch the video.

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