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.
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.
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.
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.
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
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)
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.
