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.
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-2receptors. 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.
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.
