CNS-SHEZOPHRENIA -COND...

SCHIZOPHRENIA-Contd...

Schizophrenia by its nature composed of a group of disorders, involving disruption of thoughts and disintegration of personality.

Behavioral alterations thought, affect and perception are some of the symptoms.

Disturbances in thoughts are characterized as follows:-

1.Hallucinations

2.Delusions

3.Flat affect

4.Catatonic behavior(Muscular rigidity with a stupor state)  

5.Incoherent association.

Schizophrenia occur in 1 % of the population starts the onset of the symptoms usually at 15 and 45 years of age.

Etiology

1.Genetic

2.Neurophysiologic theories such as dopamine over activities at its D-2 receptors

3.Psychosocial theories.

Many of the symptoms described by the Swiss psychiatrist Eugen Bleuler(1857-1939) are nonspecific as these symptoms are also present in non-schezophrenic. He described the 4-A's as follows:-

1.Association defects

2.Affect

3.Ambivalence

4.Autism

But the specific symptoms exclusively indicating the presence of schizophrenia are:-

1. Hallucinations especially auditory involve abnormal sensory perceptions without external cause.

2. Delusions with wrong belief and doubt without logical causes. Bizarre and seemingly realistic scenes uncover in front of the eyes. The patients may often complain that they are watched by others, they are the center of talks in society, and they are unjustifiably controlled by others.

Diagnosis:-

The patient must be brought to the diagnostic room only if any three of the following symptoms persist at least for one week continuously in order to confirm the person is a patient.

1. Delusions-Complains bizarre scenes, panic, doubts on others with obsession or withdrawal

2.Hallucinations.-Sensory perceptions

3.Incoherence

4.Catatonic look

5.Grossly inappropriate affect.

6.If he suffered from lack of self-care

7. Continuous signs of abnormalities are present at least for six months.

8.Autism 

Classifications of Schizophrenia:-

1. Disorganized -or hebephrenic schizophrenia is characterized by marked incoherence and unresponsiveness of the patient

2. Catatonic-schizophrenia is characterized by rigidity, immobility, posture, silence, and other psychomotor effects.

3.Paranoid-Characters of delusions of grandeur or persecution with obsession and aggressiveness. The patient in this class is extremely violent.

4. Undifferentiated-This type of schizophrenia is characterized by prominent delusions, hallucinations, and disorganized behavior. Altogether this class contains an overall picture of mixed behavior. Some times it may escape from diagnosis by the presence only one symptom.

5. Residual-This designates a patient who not currently psychotic but has a history of one prior episode of prominent psychotic symptoms.

Residual symptoms such as withdrawal, vague association, illogical thinking, the inappropriate effect may impair daily living skills.

ANTI-PSYCHOTIC DRUGS

TRADITIONAL DRUGS:-

Phenothiazines:-

1.Chlorpromazine

2.Fluphenazine

3.Trifluoperazine

4.Thioridazine

5.Perphenazine

The distinctive side effects of thioridazine are 1.Primary retinopathy;2.Arrhythmias;3.Conduction block.

Butyrophenones:-

1.Haloperidol

2.Droperidol

Side effects of these drugs are mainlyExtrapyramidal effects;

Dibenzoxazepines:-

Loxapine

Thioxanthenes:-

Thiothixexne

Therapeutical Uses of Traditional Drugs:-

Traditional neuroleptics can be used therapeutically as follows:-

1.Agitated states, such as schizophrenia

2.Emesis-By blocking the Dopamine receptor at the vomiting center(Chemo Receptor Trigger Zone).However, thioridazine should not be used for this purpose.

3. Tourette's syndrome (a characteristic neurological disorder onset from the childhood characterized by stereotyped behavior with abnormal vocal sounds like tics)-Haloperidol is the drug of choice

4.Interactive hiccups-Chlorpromazine

5. Antipruritic therapy-Promethazine is used because of its antihistaminic effects.

Toxicology of Neuroleptics:-

1.Sedation

2.Extrapyramidal effects

3.Anticholinergic effects(Dry mouth, blurred vision, constipation, urinary retention, and further refer to cholinergic antagonists)

4.Alpha-adrenergic effects (Contraindicated to prostatic enlargement, hypotension, and further refer to Adrenergic Agonists)

High potency drugs such as haloperidol and fluphenazine produce severe extrapyramidal effects.

Low potency drugs such as thioridazine and chlorpromazine produce highest anticholinergic effects

5. Endocrine defects can cause galactorrhea, amenorrhea, and infertility due to blockade of dopamine release from the pituitary. 

Extrapyramidal Effects:-

In general, the dopamine pathways blockade can cause prominent extrapyramidal effects as follows:-

1.Akathesia-Motor restlessness

2.Parkinson's disease-Bradykinesia

3. Dystonia-slow, prolonged muscle spasms of tongue, neck, and face)

4. Neuroleptic Malignant syndrome-This is also caused by prolonged treatments with neuroleptics. It is characterized by rigidity, altered mental status, cardiac arrhythmias, hypertension, and life-threatening hyperpyrexia. The disorder is best treated with Dantrolene a skeletal muscle relaxant.

5.Tardive dyskinesia-rhythmical involuntary movements of the tongue, lips or jaw.

The patient may demonstrate the puckering of the mouth or chewing movements.

Tardive dyskinesia is a common side effect with prolonged treatments with traditional antipsychotic drugs such as 6 months to 1-year use.

Withdrawing the treatment may cause a partial reversal of the condition but however, in many cases tardive dyskinesia is proved as irreversible.

CNS-PART-III-PSYCHOSES-SCHEZOPHRENIA-TREATMENTS

SCHIZOPHRENIA-TREATMENTS-INTRODUCTION

Psychoses are the obsessively positive or negative states of mental condition which comprise of schizophrenia, delusions, and hallucinations.

There are drugs known as neuroleptics are primarily used to treat psychoses.

Dopamine the central excitatory neurotransmitter is having several pathways in the system. If it gets overactive especially at receptors in its mesocortical pathway leads to the negative and cognitive symptoms of schizophrenia and in its mesolimbic pathways which leads to the positive and obsessive symptoms of schizophrenia.

Mechanisms of Actions:-

The main target of antipsychotics to correct psychoses is acting on the two dopaminergic pathways of the mesocortical and the mesolimbic regions, particularly upon the D-2  receptors. The overactivity of dopamine in these receptors is blocked by these drugs to correct the psychoses.

Potency Differences:-

The antipsychotic drugs differing in potencies depending upon their affinity to the D-2 receptors.

Haloperidol and thiothixene have higher potency because of their higher affinity to the D-2 receptors. In contrast, chlorpromazine and thioridazine have lower potency as their affinity for D-2 receptors is lower. But all of them are equally efficacious as they produce the same effects at their dosage calculated according to their potency. A high potent drug brings the effect at a low dosage and vice versa

Administration:-

By orally or intramuscularly.

Kinetics:-

They are absorbed in different degrees by oral routes and readily enters into the blood-brain barrier and distributed in large in various tissue compartments. This volume is further enlarged by the intramuscular route.

All drugs are metabolized in the liver by the induction of Cytochrome P-450 enzyme and hence any drug which is competitively metabolized by this enzyme may affect the effectiveness of the drug if given concomitantly.

All neuroleptic drugs may not become apparently active therapeutically immediately after administration until several weeks, but their sedative effect may onset rapidly.

Schizophrenia by nature cannot be cured but can be controlled by antipsychotic drugs.

 

 

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)