CENTRAL NERVOUS SYSTEM-ANXIETY-Contd...

BARBITURATES AND OTHER SEDATIVES-ANXIETY TREATMENTS-Contd...

In general barbiturates, the derivatives of barbituric acid are reversibly depressing all excitable tissues in CNS. The barbiturates which contain a phenyl radical such as phenobarbital can be used as antiepileptics and anesthetic. Barbiturates usage for relieving anxiety is mostly replaced by benzodiazepines because of the safety issue.

Examples are,

1.Phenobarbital (Cardinal, Luminal)-Long acting

2.Pentobarbital (Nembutal)-Short acting

3.Amobarbital-Short acting

4.Thiopental-Ultra short-acting.

Mechanism:-

Barbiturates enhance the binding of GABA on its receptor by itself binding at GABA-A receptor and thereby increase the inward conduction of chloride ion into the neuronal cell and make hyperpolarised to become relaxed, and thereby produce sedation. Remember barbiturates do not bind to the benzodiazepine receptor which is adjacent to GABA receptor. But barbiturates enhances the benzodiazepine activity if given concomitantly and produce dangerous irreversible respiratory depression and coma.

Therapeutic Uses:-

1.Induction of anesthesia-Thiopental, because of its ultra-short action anesthesia can be safely induced to its first stage-induction.

2. Anticonvulsants- Phenobarbital-which because of its phenyl radical at the fifth position of the structure can effectively control the seizures.

3.Treatment of anxiety-Mostly replaced by benzodiazepines

4.Induction of hypnosis.

Route of administrations:-

1.Intravenous-I.V.

2.Oral            -P.O

3.Intra muscular-I.M.

Kinetics:-

Barbiturates are metabolized in the liver and excreted by kidneys.

Thiopental is ultra shortly acting because of its rapid redistribution to other tissues and hence its dosage should be determined accordingly.

Drug Abuse:-

Misuse of the drug would result in drug abuse and dependence. Ataxia and confusion may result. Abrupt withdrawal may give rise to serious symptoms like tremor, palpitation, restlessness, nausea, seizures, respiratory depressions, coma, and cardiac arrest.

Contraindications:-

1.Acute porphyria because barbiturates increase porphyrin a haem pigment available in red blood cells. Barbiturates interfere with the metabolism of porphyrin and produce serious consequences like mental depression.

Adverse effects:-

1.Drowsiness and depression.

2.Decreased motor control

3.Induction of cytochrome p-450 enzyme in the liver. Concomitant administration of drugs like cimetidine, ketoconazole, etc may need double dosage as they are metabolized by this enzyme.

4.Addiction.

5.Respiratory depression and coma.

6.Allergic reactions especially in patients with asthma.

ZOLPIDEM (Ambien)

Zolpidem is another newer class of drug used in anxiety.

Mostly it is a safe medicine to treat insomnia.

It is an imidazopyridine compound a nonbenzodiazepine used to treat insomnia

It is acting on the GABA-A receptor and thereby enhance the GABA activity of greater inward conductance of chloride ions into the neuronal cell and thereby make it hyperpolarised and to become inhibited.

Use

Insomnia-Sleeplessness

Side effects

1.Ataxia

2.Confusion.

CHLORAL HYDRATE

Chloral hydrate is widely used in children to produce hypnosis and sedation.

Side effects

1.Nausea and Vomiting

2.Unpleasant taste.

 

CENTRAL NERVOUS SYSTEM-ANXIETY-CONTINUE

CNS-ANXIETY-TREATMENTS-CONTD...

1.AZASPIRONES

Buspirone:-

Buspirone is an anxiolytic with minimum side effects with a slow onset of actions such as a minimum of 2 weeks to give apparent actions.

Mechanism:-

Buspirone unlike benzodiazepines and GABA it stimulates partially the serotonin (5-hydro tryptamine) 5-HT-1A receptor which by partial agonism produces calmness.

Uses

For generalized anxiety with minimum side effects because of its slow onset of action and lack of withdrawal symptoms.

Metabolism:-

The drug is metabolized in the liver and excreted by kidneys.

I have a moderate duration of action as its half-life is 11 hours maximum.

It differs from benzodiazepines by the lack of muscle relaxant action and anticonvulsant properties.

It cannot be used like diazepam for seizures and epilepsy.

Side effects:-

1.Headaches

2.Nausea

3.Vomiting

Advantages:-

1.Less sedation

2.Low drug abuse potential

3.No overdosage fatalities

4.No withdrawal symptoms

2.CARBONATES:-

Meprobamate:-

Its mechanism of action is unknown.

These medicines totally out of use in the medical field because of its serious side effects.

Side effects:-

1.Respiratory Depression-very serious

2.Hypotension

3.Shock

4.Heart Failure.

 

CENTRAL NERVOUS SYSTEM-PART-II-ANXIETY-TREATMENTS

ANXIETY-TREATMENTS

Anxiety is an unpleasant state of emotion that consists of apprehension, tension and feelings of danger without a real cause.

Symptoms of Anxiety:-

1.Tachycardia (Increased heartbeats)

2.Tachypnea (Fast and short breathings)

3.Sweating

4.Trembling

5.Weakness

Treatments:-

Classifications of Drugs:-

1.Benzodiazepines:-

A. Short-Acting:-(2 to 8 hours)

1.Oxazepam

2.Clonazepam

3.Midazolam

4.Triazolam

B. Medium Acting:-(10 to 20 hours)

1.Temazepam

2.Lorazepam

3.Alprazolam 

C. Long-Acting:-(1 to 3 days)

1.Chlordiazepoxide

2.Diazepam

3.Flurazepam

All the above-mentioned benzodiazepines are acted by binding with its own receptors in the CNS very adjacent to GABA receptor the inhibitory neurotransmitter. Benzodiazepines enhance and potentiate the binding of GABA at its receptor.

Binding of GABA at its receptors results in chloride ion channel opening and its conductance to get the nerve hyperpolarized and prevention of the action potentials leads to nerve relaxation.

Clinical Uses:-

Major uses are as muscle relaxants followed by

1.Anxiety

2.Panic disorders(Alprazolam )

3.Status epilepticus(Diazepam)

4.Insomnia(Lorazepam, and temazepam)

5.Alcohol withdrawal (Diazepam)

Benzodiazepines can be administered by oral,i.m., and I.V. routes.

Metabolism:-

Benzodiazepines are metabolized in the liver and excreted in Urine. Many of them are having metabolites.

Tolerance and Dependence:-

Long time use may result in dependence.

Abrupt withdrawal may lead to,

1.Confusion

2.Anxiety

3.Agitation

4.Agitation

Side effects:-

1.Drowsiness and Confusion

2.Ataxia

3.Dizziness

Contraindication:-

Alcohol-If takes with alcohol serious respiratory depression followed by death.

Antidote For Benzo-Poisoning:-

Flumazenil which has a similar structure of benzodiazepines and competitively inhibits the actions of benzodiazepines at its receptors. Thus it will reverse the effects of benzodiazepine overdose.

The effects may be lost within one hour and repeated doses may be required.

CENTRAL NERVOUS SYSTEN-THE CNS-PART-I

THE BRAIN SYSTEM-INTRODUCTORY

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.

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.