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.