Central Nervous System which is originating from the Big Brain known as the Cerebrum is the major nervous system of our body. Unlike Autonomic Nervous System the CNS has many nerve transmitters, synapses, and a large array of inhibitory neurons.
The major nerve transmitters and their characters are as follows:-
1.Acetylcholine-Excitatory
2.Norepinephrine-Excitatory
3.Dopamine-Excitatory
4.Serotonin-Excitatory
5.Gamma Amino Butyric Acid (GABA), a neutral amino acid-Inhibitory
6.Glycine, an amino acetic acid, neutral,-Inhibitory
7.Aspartic Acid, an acidic amino acid-Excitatory
8.Glutamic Acid, an acidic aminoacid-Excitatory
Unlike in ANS which contains mostly G-coupled receptors, in CNS most of the receptors are ion gated receptors of sodium, potassium, calcium and chloride ions, like Na+, K+, Ca++, and Cl- respectively.
Excitation of a nerve initiated by the binding of an excitatory neurotransmitter at its receptors and opening the depolarizing ion gates of Na+or K+ or Ca++ to initiate an Excitatory Post Synaptic Potential(EPSP) when the nerve depolarize sufficiently to reach the threshold in order to stimulate an action potential to return to quick repolarization.
Inhibition of a nerve initiated by the action of an inhibitory neurotransmitter at its receptor and opening polarizing ion gates of Cl- to initiate an Inhibitory Post Synaptic Potential (IPSP) and the nerve depolarize insufficiently to reach the threshold in order to inhibit an action potential to delay the repolarization and the nerve becomes relaxed.
Drugs acting on CNS are affecting the production, storage, release, or metabolism of a neurotransmitter. Some drugs affect the postsynaptic receptors as mimics or 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.
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.)
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.
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.
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.
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.
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 bronchospasmas 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.
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
