AUTONOMIC NERVOUS SYSTEM-PART-XI-BETA BLOCKERS

BETA ADRENERGIC BLOCKERS

Drugs included in this category are having more significant medical value as most of these drugs are used as life-saving medicines in the treatments and prevention of various cardiovascular diseases.

Beta-adrenergic receptors are situated at the synapses of the postganglionic nervous system similar to alpha receptors. Unlike alpha receptors, they are mostly scattered in the cardiovascular and pulmonary systems.

Sub Classifications:-

All the beta-blockers are competitive antagonists. However, they can be sub-grouped according to three major properties.

1.The selectivity of receptor blockade

2.Possession of intrinsic sympathomimetic activities

3. Capacity to block alpha receptors.

A.Beta-1 Selective Blockers:-

1.Atenolol (Tenormin, Aten)

2.Esmolol

3.Acebutolol

4.Metoprolol (Lopressor)

In general in beta-blockers, the drug by name starting with 'A' or' M is mostly cardioselective

The drugs in this category are grouped as beta-1 selective but they have minor or negligible effects on beta-2 receptors at normal or therapeutic dosage. At toxic or high dosage they have a marked blockade effect on beta -2 receptors.

Beta-2 receptors are more scattered in the pulmonary(Lungs) system and hence beta-2 blockade may result in bronchial congestion and give unwanted results to the asthmatic patients. Also, beta-2 blockade may result in hypoglycemia. Hence care should be taken when calculating a therapeutic dosage of the beta-1 cardioselective blocker.

Therapeutical Indications

1.For Atenolol-Hypertension, Myocardial Infarction

2. For Esmolol-As esmolol's action is quick but with a very short duration (10 mins) it is used for emergency situations like thyroid storm. It should be given intravenous route(I.V.)

3.For Acebutol- Hypertension.

Metoprolol- Hypertension,Angina,Myocardial infarction.

B.Non-Selective Beta-Blockers:-

In this category propranolol is the best example.

Pharmacological Effects:-

1.Decreased cardiac output and blood pressure

2.Reduction of the sinus rate and conduction through the atria

3.Peripheral vasoconstrictions

4.Bronchoconstrictions

5.Hypoglycemia due to decreased glycogenolysis at liver

6.Counter effects by decreased glucagon secretions at the pancreas

6.Increased VLDL and decreased HDL.

Kinetics of Propranolol:-

Propranolol is well absorbed orally, but only one-fourth of the absorbed drug reaches the systemic circulation as most of them are metabolized by the liver as the first-pass metabolism.

Clinical Uses:-

1.Hypertension

2.Angina 

3.Tachycardia

4.Arrhythmia

5.Thyroid storm

6.Acute panic syndrome

7.Migraine

8.Tremors

The other examples in this nonselective beta-blockade are Timolol and Nadolol. These drugs are having a long half-life. Their duration of action is at least 20 hours.

Therapeutics:-

Timolol and nadolol are mostly used in eye preparations in glaucoma. Because of their long duration, they reduce the aqueous humor production in the eyes by the cilia muscle (beta-2 blockade) very well.

Side effects of nonselective beta-blockers:-

1.Bradycardia

2.Bronchoconstrictions

3. Confuse the tachycardia effects of hypoglycemia and hence these drugs make difficult to monitor diabetics

4.Tiredness

5.Depression

6.Gynecomastia decreased libido and sexual dysfunction

C.Beta-Blockers with Partial Sympathomimetic Activities.

These drugs by nature are adrenergic partial agonists of beta receptors. This partial agonist does not produce full agonism effects instead it will cause a receptor blockade with partial agonism. These drugs because of this partial blockade will not produce some of the side effects that are caused by full agonists or antagonists.

They will not cause bronchoconstriction at a normal dosage.

Acebutolol and Pindolol:-

These two are known examples of this classification.

They are non-selective.

Clinical use:- 

Treatment of hypertension in asthmatic patients and those who are prone to get bradycardia

Also, they have the advantage of not interfere with lipid and glucose metabolism.

D.Beta-blockers with Alpha Blocking Effects:-

These drugs are having a beta-blocking effect with selective alpha-blocking effects.

1.Labetalol:-

The mechanism is a nonselective beta-blockade with a selective alpha blockade. The alpha-blocking effects results in peripheral vasodilation rather than vasoconstriction as with other beta-blockers.

Clinical Use:-

Hypertension with atrial fibrillation.

Side effects:-

Orthostatic hypotension

Dizziness

2.Carvedilol:-

A nonselective beta-blocker with the selective alpha-1 blockade.

Uses:-

1.Hypertension

2.Chronic Congestive Heart Failure (CHF) as they improve diastolic dysfunctions by improving diastolic filling time. The advantage is they reduce sympathetic activity while correcting the BP.

Contraindications:-

While using beta-blockers in patients to treat CHF care should be taken as they may worsen the condition if the patient is not otherwise hemodynamically stable means the patient should not have any blood circulation problems.

E.Indirect Adrenergic Blockers:-

These drugs do not directly block the adrenergic receptors but they may cause interference with the availability of noradrenaline the prototype sympathetic stimulant at the receptors.

1.Guanethidine:-

This drug enters the peripheral adrenergic nerves by a reuptake mechanism (maybe due to the stimulation of presynaptic alpha-2 receptors) and bind to storage vesicles and block the release of norepinephrine from the store.

Uses:-

Hypertension

Side effects:-

1.Orthostatic Hypotension

2.Sexual dysfunction.

2.Reserpine:-

It is an alkaloid of the plant Rauwolfia serpentina.

Unlike guanethidine reserpine block the transport of norepinephrine from its place of synthesis that is cytoplasm to its storage and thereby causes unavailability of the stimulant at the receptor. Like guanethidine, it may also stimulate the presynaptic alpha-2 receptor in order to have an entry into the nerve cell by a reuptake mechanism.

Uses:-

Hypertension (Very rare)

 

AUTONOMIC NERVOUS SYSTEM-PART-X

ADRENERGIC(SYMPATHETIC)BLOCKERS

In this post, we deal with those drugs which antagonize or block the adrenergic receptors at the postganglionic sympathetic nervous system directly or indirectly.

Remember antagonizing or blocking the adrenergic postganglionic receptors will result in unopposed domination of cholinergic postganglionic effects.

General Mechanism of these drugs is that they block the intracellular response by binding at the adrenergic receptors.

Classifications 

1.Alpha-blockers

2.Beta-blockers

3.Indirect acting

Alpha (a) Blockers

1.Prazosin, Terazosin, Doxazosin,and Tamsulosin

These compounds selectively and competitively block the alpha-1 adrenergic receptors.

Among the above, the tamsulosin is having an advantage of selectively blocking alpha-1-A receptors and thereby acting selectively on the prostate gland and not affecting blood vessels. Tamsulosin is the drug of choice in the treatment of Benign Prostate Hyperplasia (Enlargement of Prostate) with minimum side effects.

Physiological Effects Of Alpha Blockade

1. The alpha-1 blockade on vascular smooth muscles (alpha-1-B) results in vasoconstriction of arterioles and veins. This causes reduced peripheral vascular resistance followed by hypotension.

2. The blockade of the alpha-1 receptor in prostate and urinary bladder muscles (alpha-1-A) results in relaxation and decreased resistance to urine flow.

Uses

1.Treatment of Hypertension

2.Enlargement of Prostate.

Side effects

1.GI hypermotility because of the unopposed cholinergic effects.

2.Orthostatic hypotension especially after the initial dose. This effect is nill or negligible with tamsulosin because of its selectivity on alpha-1-B receptors.

3.Sexual defects

4.Dry mouth 

5.Dizziness

2.Phenoxybenzamine

It is unique in action by non competitively block both presynaptic (alpha-2) and postsynaptic(alpha-1) receptors. The effect on the alpha-2 receptor is very little or negligible.

Because of this unique action of blocking presynaptic alpha-2 blockade, it causes a partial sympathomimetic activity by preventing noradrenaline reabsorption at the presynaptic level but is minor importance. Hence it causes peripheral vasodilation and reflex tachycardia.

Administered by mouth.

This drug acting on the receptor noncompetitively by strong covalent bonds and hence it has a prolonged duration of action up to 14 hours.

Therapeutics

1.Treatment of Pheochromocytoma induced hypertension.

Pheochromocytoma is a tumor that occurs in the adrenal gland. Because of the tumor, the gland gets hyperstimulation to release excess catecholamines like adrenaline and noradrenaline which causes a hypertensive crisis for which Phenoxybenzamine is the drug of choice because of its long duration of actions.

2. Treatment of BPH as uniquely this drug reduces the size of the prostate along with its hypotensive effects. But be careful about its other side effects.

3.In spinal cord injuries which causes hyperreflexia that results in elevated blood pressure. Phenoxybenzamine blunts these effects.

4. Treatment of Reynaud's disease, in which there is reduced blood flow at the fingertips causes numbness in response to high cold weather or stress.

Side effects

1.Orthostatic hypotension

2. Reflex tachycardia-hence it may cause anginal pain and contraindicate in patients with CHD.

3.Inhibition of ejaculation due to over-relaxation of smooth muscles in vas deferens

3.Yohimbine

It is selective alpha-2 presynaptic receptors that cause excessive collection of noradrenalin at the synapsis as a result of the adrenergic crisis.

It is sometimes used to treat impotency by direct penile injection.

This drug in lower dosage block majorly the alpha-2 receptor only and cause hypertension but in higher dosage, it blocks alpha-1 receptors predominantly and causes serious hypotension.

4.Phentolamine

It is an imidazole compound.

It reversibly blocks alpha-1and alpha-2 receptors

Hence the effects are with dosage adjustments. As this drug primarily block alpha-1 receptors at low dosages and hence causes hypotension. But in high doses, it blocks alpha-2 also and may cause hypertension.

It can be administered by I.V and I.M as poor absorption orally.

Uses

Because of its short duration of action (4 hours), it can be used for short courses of pheochromocytoma induced hypertension in low dosages.

Side effects

1.Orthostatic hypotension in low doses.

2.Peptic ulcer due to GI hypermotility due to unopposed cholinergic effects.

3.Tachycardia-due to reflex adrenergic response

4.Heart attacks-,,,,,,

5.Arrhythmias -,,,,,,

AUTONOMIC NERVOUS SYSEM-PART-IX

MIXED (DIRECT AND INDIRECT) AGONISTS

These drugs act indirectly by releasing noradrenaline from its storage as well as directly act at the receptors.

1.Ephedrine:-

Ephedrine according to its classification releases noradrenaline from its storage vesicles and thereby stimulating the adrenergic postganglionic receptors. Also, ephedrine acts directly at the receptor sites and causes sympathetic stimulation.

Uses:-

1.Urinary incontinence (Frequent and involuntary urinations)

2.Bronchospasm as in asthma or Congestive and Obstructive Pulmonary Disease, Bronchitis, Caugh, and Cold.

3.Hypotension.

Side effects:-

1.Arrhythmias

2.Palpitations

3.Insomnia

4.Hypertension

2.Metaraminol:-

Similar to ephedrine metaraminol also causes the release of noradrenaline to act on its receptors as well as itself acts directly on the receptors.

It is having an affinity adrenergic alpha receptors.

Uses:-

1.Treatment of hypotension

2. Termination of Paroxysmal Atrial Tachycardia(PAT) is a kind acute tachyarrhythmia that starts quickly at the atria and ends quickly. It is also known as Bouveret Hoffman Syndrome

Side effects:-

1.Hypertension

2.Palpitations

3.Urinary retention

4.Insomnia

5.Arrhythmias

and all other symptoms similar to that of adrenergic stimulations.

AUTONOMIC NERVOUS SYSTEM-PART-VIII

ADRENERGIC AGONISTS-INDIRECT

These drugs are indirectly stimulating the adrenergic nerves by causing the release of catecholamines (mainly noradrenaline).

1.Tyramine:-

Tyramine is a byproduct of tyrosine metabolism and tyrosine is the precursor for dopamine, epinephrine, and norepinephrine. Tyramine on ingestion can release catecholamines such as norepinephrine, epinephrine, and dopamine from their storage vesicles. However, tyramine cannot cross the blood-brain barrier but can cause peripheral sympathetic hypertensive crisis and headaches if taken along with a Monoamine Oxidase Inhibitor (MAOI) as it is mainly metabolized by the enzyme MAO.

Hence because of this effect, those who are taking MAOI should not take tyramine rich foods such as spoiled or decayed meats, fish, pork, poultry, beef, cheese, chocolate, and alcoholic beverages.

Recent researches have proved that tyramine has a little directly acting effect at the postganglionic adrenergic receptors and it can cross the blood-brain barrier.

Tyramine has no therapeutic values so for.

Toxicity

1.Hypertensive crisis in those who consume MAOIs since tyramine is compromised by these drugs by preventing its metabolism by MAO.

Hence these people should avoid taking foods such as red wine, beer, chocolate, cheese, and decayed meats.

2.Amphetamine 

Similar to tyramine it releases the stored catecholamines such as norepinephrine and dopamine from their storage.

It can readily cross into the blood-brain barrier and produce serious CNS effects, such as sleeplessness, dizziness, etc.

Amphetamine is clinically used to treat,

1.Attention Deficit Hyperactivity Disorder(ADHD) 2.Narcolepsy, a chronic neurological disorder in which there is a loss of brain control over the sleep-wake cycles.

3.Appetite suppression.

Toxicology

1.Psychological and physical dependence

2.Psychoses

3.Confusion

4.Insomnia

5.Headache

6.Restlessness

7.Palpitations

8.Tachycardia

9.Impotence

 

AUTONOMIC NERVOUS SYSTEM-PART-VII

DIRECT ACTING ALPHA, BETA AGONISTS

These drugs acting on the adrenergic receptors directly. They mimic the actions of noradrenaline.

1.Epinephrine(Adrenaline)

Epinephrine act on alpha-1,alpha-2;and beta-1,beta-2 receptors in a proportionate manner.

In low dosage, it is effective to stimulate the beta-receptors and at high doses, it is effective on alpha receptors. But the alpha stimulation is predominant and persistent at high doses.

Effects of Epinephrine

1.It increases heart contractility(inotropic);heart rate(chronotropic);vasoconstrictions of arterioles in the skin,viscera,and mucus membrane (apha-1);

2.Bronchodilation due to stimulation of beta-2 receptors.

3. Increased glycogenolysis and release of glucagon and a reduced release in insulin leads to hyperglycemia.

Uses

1. To relieve bronchospasm as a secondary symptom in Asthma and Anaphylactic shock.

2.Used in anaphylactic shock and cardiac arrest to increase the electrical conductivity through the pacemaker AV and SA nodes and Purkinje fibers (Dronotropic effects)

3.In conjunction with local anesthetics to prolong the local effects by local vasoconstriction effects.

4. To achieve hemostasis.

Side effects

1.Arrhythmias

2.Hypertension

3.Palpitations

4.Dizziness, anxiety, headache

5.Myocardial Infarction due to heavy workload on the heart.

6.Pulmonary edema.

Epinephrine Reversal 

Interestingly if epinephrine is given alone it increases the systemic blood pressure due to its alpha vasoconstriction effects. If given along with an alpha-blocker such as phenoxybenzamine it will lower the blood pressure due to its beta smooth muscle-relaxing effects. This action is technically known as Adrenaline Reversal.

2.Nor Epinephrine-Nor Adrenaline 

Noradrenaline the main prototype nerve transmitter stimulates alpha-1,alpha-2, and beta-1 receptors with a stronger affinity for alpha receptors than for beta receptors.

Its main physiologic effects are vasoconstriction, Reflux bradycardia

It is one of the last line agents in the treatment of shock.

Side effects

1.Tissue hypoxia secondary to potent vasoconstriction

2.Decreased perfusion to the kidneys

3.Tissue necrosis due to extravasation during I.V. administration.

4.Arrhythmia

3.Dopamine

This drug is synthesized in the CNS, sympathetic ganglia and adrenal medulla.

Dopamine act on alpha-1,beta-1, and beta-2 receptors with a greater affinity towards dopamine and beta receptors. It also acts on its own receptors D-1 and D-2 receptors located in the peripheral mesenteric and renal vascular beds.

Dopamine at its low dose stimulates dopamine receptors, at moderate dose beta receptors and at high dose alpha-1 receptors. Dopamine is highly polar, hydrophilic, and does not cross the blood-brain barrier.

Uses

1. Treatment of shock-It raises blood pressure by increasing the heart rate by stimulating the beta-1 receptors

2. In acute renal failure, dopamine is used to increase renal blood flow.

3.Treatment of acute congestive heart failure.

Administered through I.V.

Side effects

1.Decreased renal perfusion a higher doses

2.Arrhythmias

3.Tachycardia

4.Hypertension

5. Tissue necrosis may occur if dopamine extravasates during I.V.infusion. 

 

 

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 

 

 

 

 

 

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.