drugs and the treatment of psychiatric disorders

Drugs in the treatment of psychiatric disorders

• Causes sedation, stimulation , change mood,thinking or behavior.

• many drugs used for other purpose also modify emotions and cognition either as part of their usual actions or as toxic effects of overdosage.

Classification of psychotropic agents

• Antipsychotic or neuroleptic drugs: to treat very severe psychiatric illness, psychoses and mania.

• Antianxiety-sedative agents :to treat anxiety disorders.

• Antidepressants and antimanic drugs: to treat affective or mood disorders and related conditions.

– In 1845, Moreau proposed that marijuana intoxication provided a model of psychosis ,useful in the study of insanity.

– Three decades later, Freud presented his study of cocaine and suggested its potential uses in pharmacotherapy.

History

– In 1931, Sen and Bose published the first report of the use of Rauwolfia Serpentina in the treatment of insanity.

– In 1943, Hofmann ingested a minute amount of the ergot derivative lysergic acid diethylamide (LSD) and experienced its hallucinogenic effects.

Dr. Hofmann

The first modern report on the treatment of psychotic excitement or mania with lithium salts was that of Cade(1949).because of concerns about the toxic effects of lithium ,this discovery was slow in gaining general acceptance by the medical community.

– In 1950,chlorpromazine was synthesized in France. the recognition of the unique effects of chlorpromazine by Laborit and colleagues(1952) and its use in psychiatric patients by Delay and Deniker (1952) marks the beginnings of modern psychopharmacology.

• The psychoses are among the most severe psychiatric disorders ,in which there is not only marked impairment of behavior but also a serious inability to think coherently, to comprehend reality , or to gain insight into the presence of these abnormalities.

– The psychoses commonly include symptoms of false beliefs (delusions) and abnormal sensations (hallucinations).

• The major disorders of mood or affect include the syndromes of major depression and biopolar disorder( formerly manic-depressive disorder). They commonly included disordered autonomic functioning and behavior , as well as persistent abnormalities of mood and increased risk of self-harm or suicide.

• A leading hypothesis that aroused from such considerations was based on observation indicating that antidepressants enhance the biological activity of monoamine neurotransmitters in CNS and that antiadrenergic compounds may induce depression.

• These observation led to speculation that a deficiency of aminergic transmission in the CNS might be causative of depression or that an excess could result in mania.

$1 Drugs used in the treatment of psychosis

• Effective antipsychotic compounds include the phenothiazines, thioxanthenes, butyrophenones, and other antipsychotic agents.

History • In the early 1950s, it was fo

und that reserpine deplete monoamines from their vesicular storage site in neurons and then exert antipsychotic effects ,these are relatively weak and are typically associated with severe side effects ,including sedation, hypotension ,diarrhea, faintness, and depressed mood.

Rauwolfia plant

• Phenothiazine compounds were sythesized in Europe in the late 19th century. In the late 1930s a phenothiazide derivative, promethazine, was found to have antihistaminic and sedative effects.

• In 1949~1950, Charpentier synthesized chlorpromazine .soon thereafter ,Laborit and colleagues described the ability of this compound to potentiate anesthetics and produce artificial hibernation.

• The first attempts to treat mental illness with chlorpromazine were made in Paris in 1951. In 1952,Delay and Deniker convinced that chlorpromazine achieved more than symptomatic relief agitation or anxiety .

• Clinical studies soon reveal that chlorpromazine was effective in the treatment of psychotic of various types.

PhenothiazinesDrug Major use Frequency of Adverse Effects

Orthostatic Extrapyramidal

　 　 Hypotension Symptoms

Chlorpromazine Antipsychotic Moderate Moderate

Antiemetic

Clozapine Antipsychotic Low Low

Anticholinergic

Antihistaminic

Thioridazine Antipsychotic Moderate Low

Triflupromazine Antipsychotic Moderate High

Fluphenazine Antipsychotic Low High

Prochlorperazine Antiemtic Low Low-moderate

Promethazine Antihistaminic Moderate Low

Pharmacological effects

• The effects are believed to be due to antagonism of dopaminergic receptor in CNS.– DA receptor blockade in limibic system-mesencephalic pathw

ay: improvement of emotion.– DA receptor blokade in cortico-mesencephalic pathway: resto

ration of thinking and emotion.– DA receptor blokade in nigrostriatum pathway :causing extra

pyramidal symptoms.– DA receptor blokade in hypothalamo-hypophtsis pathway: ca

using endocrine dysfunction.

• CNS effects– Antipsychotic effects

• Tranquilization : phenothiazines making animals docile and friendly, rapidly control manic states of psychotic patients and make them quiet and peaceful ,make patients feel indifferent , then induce sleep.

In human beings, neuroleptic drugs reduce initiative and interest in the environment , as well as manifestation of emotion or affect. aggressive and impulsive behavior diminishes. Gradually, psychotic symptom of hallucinations, delusions, and disorganized or incoherent thinking tend to disappear.

•Restoration of intellect, emotional quieting and reducing psychomotor excitement in few weeks.

•Elimination of hallucinations and delusions in few month.

The clinical symptoms of schizophrenia are related to hyperfunction of doparminergic nerve due to the increase of DA receptors in the brain. Phenothiazines produce a antipsychotic effect via blocking DA receptor in limbic system-mesencephalic and cortico-mesencephalic pathway.

Sedation and synergism with other CNS depressives( analgesics, sedative-hypnotics, anesthetics): phenothiazines are known to enhance the pharmacological actions of barbiturate, narcotics and ethyl alcohol.

Antiemetic effects:The agents block DA recepto

rs in medullary CTZ to inhibit vomiting with low doses.

In high doses, the agents may directly depress the medullary vomiting center.

•Effects on temperature-regulation mechanism–They inhibit temperature-regulating center in hypothalamus, including hypothermia in a cold environment ;however, they can cause hyperthermia in a hot climate.

• Altering endocrine system: since phenothiazines depress the hypothalamus by blocking DA receptors, endocrine alteration may occur.

– This includes the release of prolactin to induce lactation and gynecomastia.

– abnormal pigmentation can occur because of an increased release of melanocyte-stimulating hormone from the pituitary.

– Phenothiazines decrease corticotropin release and secretion of pituitary growth hormone

– Weight gain and increased appetite are seen.

• Peripheral effects– An α-adrenergic blocking activity is

seen, especially with the prototypic phenothiazine , chlorpromazine.

– Anticholinergic effects can result in blurred vision, constipation, dry mouth, decreased sweating and rarely urinary retention. Miosis is seen with chlorpromazine and is probably due to adrenergic blockade. Other phenothiazines can produce mydriasis.

Clinical uses

• Phenothiazines are chiefly used in the treatment of psychotic disorders , including mania, paranoid states, schizophrenia ,and psychoses associated with chronic alcoholism.

• Several Phenothiazines are effective in the treatment of nausea and vomiting include by certain diseases, some drugs, cancers, and radiation etc. but, they are ineffective for vomiting induced by stimulating vestibules of ears.

• Artificial hibernation. Lyticccocktail (chlorpromazine + dolantin +promethazine) and physical reduction of body temperature can reduce the body temperature below normal level.

Body temperature ↓

Irritability to pathologic reaction ↓

Basal metabolism ↓→O2 consumption↓

Vasodilation →microcirculation↑

Protecting the important organs from damage( symptomatic treatment) to gain enough time for effective etiological treatment. Artificial hibernation therapy can be used in serious patients with toxic infection, intoxication and trauma etc.

• Due to their H1 antihistamic activity , some phenothiazines are useful as antipruritics.

• Chlorpromazine is useful in the control of intractable hiccup.

pruritics

Pharmacokinetics

Absorption :oral administration. Intramuscular administration increases the bioavailability of active drug by four to ten times. The drug are highly lipophilic ,highly membrane-or protein-bound , and accumulate in the brain, lung, and other tissues with a high blood supply. they also enter the fetal circulation and breast milk.

• Distribution :T1/2:20~40hs• Biotransformation and excretion: the main

routes of metabolism of the antipsychotic drugs are oxidative processes mediated largely by genetically controlled hepatic microsomal oxidases and conjugation processes. hydrophilic metabolites of these drugs are excreted in the urine and ,to some extent, in the bile.

Adverse effects

• General adverse effects: dry mouth, constipation, blurred vision etc.

• Extrapyramidal effects– A parkinsonian syndrome may occur in which patie

nts display rigidity and tremor at rest.– Acute dystonic reaction may be seen with initial dr

ug therapy: facial grimacing and torticollis.

Tardive dyskinesia maybe seen with chronic tharapy.• Patients display sucking and smacking of the

lips and other involuntary facial movements. The dyskinesia may persist for some time even after discontinuation of therapy. The symptoms occur most often with chronic administration because of blocking DA receptors in the nigrostriatum. They can be treated by using an anticholinergic antiparkinsonian drugs such as Artan.

– Akathiasia: refers to strong subjective feelings of distress or discomfort, often referred to the legs, as well as to a compelling need to be in constant movement rather than to follow any specific movement.• Antianxiety agents or moderate doses of propra

nolol may be beneficial.

• Cardiovascular effects:– The effects include orthostatic hypotensi

on, which can result in coma and reflex tachycardia.

• Allergic reactions:– The reaction often occur during the first f

ew months of therapy. such as blood dyscrasias, various form of dermatitis.

Butyrophenones • The prototype is haloperidol, which resem

bles the phenothiazines pharmacologically. It has more potent antipsychotic, antiemetic and extrapyramidal properties than phenothiazines

• Another butyrophenone, droperidol , is often combined with a potent narcotic analgesic, such as fentanyl , to produce neurolept analgesia used in small surgery.

Clozapine

• Unlike standard neuroleptic and antipsychotic agents, clozapine lacks extrapyramidal side effects.

• It also differ from typical neuroleptic agents by having low affinity for DA receptors.

• Clozapine has relatively potent anticholinergic activity, antiadrenergic ,and possible antihistaminergic activity.

• Clinical uses: clozapine can be effective in treating some patients with psychosis who are unresponsive to standard neurolepic drugs. It can be used safely if granulocyte counts are monitored weekly.

Chlorprothixene( tardan) • It has less potent antipsychotic activity, more

potent sedative and some antidepressive effects.

• It can be used in the patients with psychosis as well as anxiety and /or depression, and also be used in neurosis with anxiety and climateric melancholia.

$2 mood-altering drugs

• Manic-depression is one of psychoses with the pathologic alternation of affection as the main symptoms, and also referred to affective disorders.

• Pathogenesis of mood disorder is thought to be related to lack of 5-HT in the brain. On the basis mentioned above, depression would be induced if NA in the brain lacks. mania would be induced if NA increases; the bipolar disorder would be induced if alternative change of NA.

• Another mechanism of action is related to lithium’s inhibition of hormone-sensitive adenylate cyclase and the greater stablization of dopamine and β-adrenergic receptors.

Clinical uses

• The major therapeutic indications are the mania and manic episodes of bipolar disorder.

• It may also be useful in reducing the intensity of depression and increasing the duration between bouts of depression in unipolar depression.

• Lithium has no effect on schizophrenia and dose not produce psychotropic effects in normal.

Adverse reaction

• Because it has a low therapeutic index, serum concentration must be carefully maintained between 0.8 and 1.5mmol/L,high serum concentration of lithium is associated with vomiting, diarrhea, excessive thirst and polyuria.

• Epileptic seizures have been reported , as well as dizziness, confusion and psychomotor disturbance.

• The use of lithium during early pregnancy can result in cardiovascular anomalies in newborn.

• Adverse cardiovascular effects include hypotension and cardiac arrythmias.

• Chronic lithium use can result in thyroid enlargement.

• Lithium intoxication can usually be reversed by osmotic diuresis or , in more severe cases, by dialysis.

Antidepressant agents

• Classification – Tricyclic antidepressants, imipramine ,a

mitriptyline, desipramine, nortriptyline ,doxepin.

– MAO inhibitors• Hydrazides: isocarboxazid, phenelzine.• Nonhydrazides : tranylcypromine• 5-HT reuptake inhibitors: Fuoxetine, sertrali

ne, paroxetine,bupropion,venlafaxine.

Tricyclic antidepressants• Mechanism of action

– Depression is an alternation of mood characterized by sadness, worry and anxiety. Most antidepressants are believed to improve mood by blocking NA and 5-HT reuptake to increase NA and 5-HT level in brain.

Pharmacological effects

• Effects on CNS – A nondepressed person experiences slee

piness when a tricyclic antidepressant is administered. In addition, anxiety and toxic anticholinergic effects may be experienced.

– In the depressed patient, an elevation of mood occurs 2~3 weeks after administration begins, the latency period can be as long as 4 weeks.

– Tricyclic antidepressants can cause extrapyramidal symptoms .

– High doses of tricyclic antidepressants are capable of producing seizures and coma.

• Cardiovascular effects– Orthostatic hypotension and arrythmias

are two common effects.– Tachycardia in response to the hypotens

ion and interference with atrioventricular conduction similar to that produced by quinidine can occur.

• Autonomic nervous system effects.– Anticholinergic effects is most common one.

Amitriptyline possesses the most potent antimuscarine effects.

Clinical uses

• These agents are considered the choice for severe endogenous depression characterized by regression and inactivity. In term of overall efficacy, the various tricyclic antidepressant are equivalent at appropriate dosages.

• Enuresis has been successfully treated with imipramine.

• Obsessive –compulsive neurosis accompanied by depression ,and phobic anxiety syndromes, and chronic pain , and neuralgia may respond to tricyclic agents; it should be noted that these indications are investigational.

Adverse effects

• Peripheral : anticholinergic action– Caution is required in treating patients with

prostatic hypertrophy and glaucoma.– sweating is common, although its mechanis

m is unkown.

• Central : the elderly may suffer from ataxia, dizziness and muscle tremor; manic excitement can occur in the patients with bipolar illness.

• Cardiovascular :cardiac arrhythmias and hypotension can occur.