CNS-PART-V-MANIA-TREATMENTS

MANIA-TREATMENTS

Mania is a kind of mental disorder just opposite to depression in which there are uncontrolled mood elevation,with practically impossible grandiose ideas,expansiveness,pressurised talks,flow of ideas,decreased sleep,restlessness,and over activities.

Schizophrenia and other bipolar affective diseases may induce mania into a person.

Anti-Manic Drugs:-

1.Lithium-Drug of choice

2.Antiepileptics-Valproic acid,and carbamazepine are he best choices.We will discuss about these drugs later on under a separate post wih the heading Antiepileptics.

Lithium:-

Lithium is a metallic basic element with a light alkaline property and mostly available in medicine as slow and controlled release carbonate.

Mechanism

The mechanism of action is still not clear but thought to affect the enzyme inositol-I-phosphate which affects neurotransmitters.

Clinical Use

Mostly to control both positive(schezophrenia and mania) and negative (Depression) bipolar mental disorders.Litghium is a primary choice of manic disorders but can be used as an adjuant in the treatments of schezophrenia and depression.

Kineics

Well absorbed orally and excreted through the kidneys.

Contraindications

Because lithium can cross into the placenta and milk it is highly contraindicated during pregnancy and lactation.

Side Effects

1.In acute intoxication severe tremor,ataxia,seizures,and confusion leads to coma ma may occur.

2.Diabetic insipidus (Lithium is a potential inhibitor of Anti Diuretic Hormone-See he video below)

3.Weight gain

4.Stomach pain and vomiting and diarrhea

5.Thyroidal dysfunction-Hypothyroidsm

6.Depression of T-waves in ECG

7.Leucocytosis (Elevation of WBC count to above normal)

In general lithium has a very narrow therapeutic index and hence all lithium medication should be taken under a doctor's strict supervision.

Drug Interaction

Since lithium competes with sodium in absorption and as well as in tubular elimination effectively  by inhibiting the antidiuretic hormone  and excessive intake of sodium may cause a dip in lithium plasma level.

Thiazide diuretics may enhance sodium excretion and thereby elevate lithium plasma level.

Toxicity Antidotes

1.Diuretics other than thiazides may decrease plasma levels of lithium by increasing its excretion.Sodium bicarbonate can be used effectively.

2.Hemo or peritonial dialysis.

CNS-DEPRESSION TREATMENS -Contd...

ANTI DEPRESSANTS-Contd...

Atypical Antidepressants:

Atypical antidepressants do not have a specific class of action but their antidepressant effects are most probably by an unknown mechanism with minimum side effects.

1.Trazadone:-

An antidepressant is structurally very similar to the benzodiazepine alprazolam but more specific in the inhibition of serotonin reuptake.

It is particularly effective in improving sleep.

It is metabolized in the liver and excreted by the kidneys.

Side Effects

1.Sedation

2.Orthostatic hypotension

3.Nausea

4.Headache and dizziness

5.Agitation

6.Anticholinergic effects(Rare)

2.Bupropion

It is also an atypical antidepressant with an unclear mechanism of action.

Side Effects

1.Headache

2.Nausea

3.Tachycardia

4.Restlessness

Fortunately, with bupropion there is no sexual dysfunction toxicity which is distinctive with SSRIs.

SSRI:-Serotonine Specific Reuptake Inhibitor

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CNS-DEPRESSION-PART-IV-Contd..

DEPRESSION-TREATMENTS-Contd...

Mono Amine Oxidase Inhibitors (MAOIs):-

Mono Amine Oxidase is a typical enzyme available widely in our body especially in the neuronal mitochondria(a small tissue composed of endothelial cells present within the nerve synapses)in the CNS, liver, and the entire digestive tract. A major portion is present in the liver. Its main duty is to decompose any monoamines(a chemical which contains only one amino -NH2- group in its molecular structure) such as all excess catecholamines neurotransmitters like norepinephrine, epinephrine, dopamine etc.etc. by oxidation. This enzyme is protecting our CNS from overstimulation by the excess monoamine neurotransmitters.

These MAOs are grouped into two as MAO-A; and MAO-B

The former is present mostly in the mitochondrial cells of CNS presynaptic nerves, liver, lungs, placenta, and GI tract. This group is responsible to deaminate(decompose) norepinephrine, epinephrine, serotonin, and melatonin.

The latter group is mainly present in the blood platelets and is responsible to decompose phenylethylamine and benzylamine.

Dopamine and tyramine are affected by both the groups with a little more effect by MAO-B

Mechanisms MAOIs:-

Within the neuronal presynapses, these inhibitors act on MAO-A and block its decomposing effect of the neurotransmitters such as norepinephrine, and serotonin and thereby cause accumulation of the transmitters sufficiently to release from the storage into the synaptic space to act on their respective receptors present at the post synapse. Similarly, blockade of MAO-B will result in the accumulation and release of Dopamine into the synapse to act on its receptor.

All MAOIs are mostly nonspecific except selegiline which specific to block MAO-B and are widely used in Parkinson's Disease in which there is insufficient dopamine present at the synapse and hence it is of little importance here.

Clinical Indications of nonspecific MAOIs:-

Atypical depression, like phobias.

Kinetics:

1. Orally well absorbed

2. Metabolized in the liver by acetylation.

MAOIs are generally having half-life 2 to 3 hours. But they require 3 to 4 weeks of treatment to attain the steady-state plasma concentration.

Side Effects:-

1.Hypertensive crisis such as headache, arrhythmias, and stroke. Hence the patient should be advised not to take tyramine rich foods like seasoned cheese, chicken liver, chocolates, beer, and red wine.

The hypertensive crisis will also occur if taken MAOIs along with any opioids such as meperidine.
2.Orthostatic hypotension
3.Anticholinergic effects such as dry mouth, blurred vision, and weight gain.

CNS-PART-IV-DEPRESSION AND MANIA-Contd...

DEPRESSION-Cond...

 

Tricyclic antidepressants and MAOIs should not be given together as the combination will seriously result in excess accumulation of catecholamines at the receptors that lead to a crisis, convulsions, and coma.

Serotonin Specific Reuptake Inhibitors (SSRIs):-

1.Fluoxetine 

2.Sertraline

3.Paroxetine

4.Fluvoxamine

Mechanism:-

These drugs increase the availability of serotonin (5-Hydroxy Tryptamine) at the synapses by inhibiting its reuptake mechanism. It has no specific effect on norepinephrine and dopamine and hence these drugs are mild and safe.

Therapeutics

1.Depression

2. Fluoxetine is used in Obsessive-Compulsive Disorder (OCD)

Route of Administration:-

By oral route.

Kinetics

They are well absorbed orally and metabolized in the liver by the induction of the enzyme Cytochrome-P-450. Fluvoxamine is exempted as it is metabolized but a powerful C P-450 inhibitor. The metabolites are excreted in the urine.

Side Effects

In general, these drugs are safer than tricyclic and traditional antidepressants as they are specific on serotonin reuptake only. They don't interfere with or inhibit the reuptake of norepinephrine and dopamine. Hence they are milder in producing anticholinergic, antihistaminic, and alpha-adrenergic blockades.

1.Nausea

2.Diarrhea

3.Nervousness

4.Insomnia

5.Dizziness

6.Impotence

7.Decreased libido.

Contraindicated:-

If used with any drug which inhibits the mitochondrial enzyme Mono Amine Oxidase which is responsible for metabolizing norepinephrine dopamine and other catecholamines, and serotonin the excess accumulation of these chemicals will leads to a crisis known as Serotonin Syndrome which leads to hyperthermia, muscle rigidity, myoclonus(spasmodic twitching of group of muscles), and rapid mental disorder.

CNS-PART-IV-DEPRESSION AND MANIA-Contd...

DEPRESSION -TREATMENTS

Here we deal with the detailed treatment options for depression.

Tricyclic Antidepressants:-

1.Tertiary Amines:-

a)Amitriptyline

b)Imipramine

c)Doxepin

d)Clomipramine

e)Trimipramine

Secondary Amines:-

a)Amoxapine

b)Maprotiline

c)Protriptyline

d)Desipramine

c)Nortriptyline

Among the above-listed drugs the secondary amines have a wider therapeutic index and safer than tertiary amines as they are effective with less sedation, hypotension, and anticholinergic effects. But they are more likely to cause schizophrenia and psychoses.

Mechanisms:-

The mechanism of actions of all tricyclics is by blocking the reuptake of norepinephrine and serotonin at the CNS synapses and thereby increase there availability and neuronal effects.

They also block histamine, cholinergic, and alpha-adrenergic receptors. The later effects of blockades account and contribute to their side effects.

Tricyclics have additional therapeutic benefits by causing the downregulation of monoamine receptors.

These drugs are not to be used as mood elevators in normal individuals as they are not CNS stimulants like caffeine.

Therapeutics:-

1.Depression

2.Panic disorders

3.Anxiety

4.Post-traumatic tension and stress.

5.Obsessive and Compulsive Disorders (Clomipramine)

6.Pain Disorders

7.Enuresis in children (Imipramine)

Route:-

Oral route.

Readily enter into the blood-brain barrier.

Kinetics

First, pass metabolism in the liver and excreted in urine as glucuronates.

Side Effects:-

1.Anticholinergic effects such as constipation,drymouth,blurred vision,confusion,and urinary retension.

2.Orthostatic hypotension.

3.Arrhythmias, and ECG changes such as the widening of the QRS angle.

4.Weight gain

5.Histamine blockade results in sedation.

6.Seizures.

 



CNS-PART-IV-DEPRESSION AND MANIA-

DEPRESSION AND MANIA

Depression is an affective syndrome characterized by intense sadness, general loss of interests in everyday aspects of life, insomnia, changes in appetite, and low self-esteem.

In the neurological point of view depression is due to lack of norepinephrine, serotonin, and dopamine at the CNS nerve synapses.

Treatments:-

1.Tricyclic antidepressants

2.Serotonin Specific Reuptake Inhibitors,(SSRIs)

3.Mono Amine Oxidase Inhibitors(MAOI)

4.Atypical or nonspecific antidepressants.

Out of the above treatments, SSRIs and atypical antidepressant treatments are considered as the most preferable and first-line treatments

CNS-ANTIPSYCHOTIC DRUGS-Contd....

ANTIPSYCHOTICS-ATYPICAL

As we have already dealt in the last post with the typical traditional neuroleptics (antipsychotics) here we will deal with some neuroleptics or antipsychotics which are not typical in action and are not only acting against dopamine but they are also acting against serotonin(5-HT) at its receptors. Moreover, they are rarely associated with extrapyramidal side effects. In general, they have a wider therapeutic index and are safer than typical neuroleptics.

The therapeutic index is the ratio between the toxic dose(the amount of the drug which can produce minimal toxicity, TD) to the effective dose(the amount of the same drug that can produce the required effect, ED).

Therapeuic Index (TI)   =  TD / ED

If the result is greater then the drug is safer. The atypical neuroleptic drugs are safer than typical neuroleptics as their toxic dose, TD (numerator) is higher than their effective dose, ED(denominator).

1.Clozapine:-

It is chemically a derivative of the compound benzodiazepine. It is a potent serotonin receptor blocker along with its normal dopamine blockade effects.

Therapeutical Uses:-

1. Clozapine is an effective way of treating schizophrenia associated with suicide mentality. It improves self-confidence. It is more effective than phenothiazines, the typical neuroleptics.

2. Also, it improves negative aspects of schizophrenia such as blunted emotions, withdrawal, reduced ability to establish relationships)

Toxicity and Acute Side Effects

1.Prolonged usage may leads to serious side effects such as decreased WBC,cardiac inflammations,agranulocytosis,bone marrow suppression,neutropenia,seizures,hypotension etc.etc.

2. Acute side effects are such as fewer extrapyramidal effects than typical neuroleptics along with constipation, bedwetting, tremor etc.etc.

2.Risperidone:-

Chemically it is a derivative of the compound Benzisoxazole.

Like clozapine this drug also has a greater blockade affinity for serotonin receptors along with its usual dopamine blocking effects.

Fortunately, these drugs have a lack of anticholinergic effects and hence they have minimal extrapyramidal side effects.

Therapeutics:-

Risperidone unlike clozapine is effective against both positive(obsessive) and negative (withdrawal) types of schizophrenia hence it is the first-line medicine.

Precaution:-

The drug is said to prolong the QT intervals in the ECG hence care should be taken with the cardiac patients with QT abnormalities.

3.Olanzapine:-

Mechanism of actions is very similar to clozapine and risperidone by blocking both 5-HT and dopamine receptors.

Uses

Schizophrenia

Side effects:-

1.Anticholinergic (refer o cholinergic antagonists)

2.Minimal extrapyramidal effects

3.Sedation

4.Orthostatic hypotension.