Anti-psychotic drugs ,Anti-depressant drugs & Anti- manic drugs

Sunday, October 10, 2010

These are the drugs which used in treatment of major psychosis

They are also called a major tranquilizers, since they reduce agitation and disturbed behavior seen in schizophrenia

1.  Phenothiazines

Chlorpromazine
Triflupromazine
Fluphenazine
Thioridazine

2. Butyrophenones

Haloperidol
Trifluperidol

3. Rauwolfia alkaloids

Reserpine


4. Thioxanthines

Chlorprothixene
Thiothixene

5. Indolic derivatives

Molindine

6. Miscellaneous

Oxypertine
Tetrabenazine
Pimozide
 
CHLORPROMAZINE  (CPZ)

These are the most widely used compounds in the treatment of major  psychoses
Phenothiazines are three ringed structures

In which two benzene rings  are linked by a sulphur and a nitrogen atom

Chlorpromazine is the important phenothiazine and was synthesized in 1950

According to the chemical structure , phenothiazines could be predominantly antipsychotic c, ant cholinergic or antihistaminic

Mechanism of action
Phenothiazines and other antipsychotic drugs produce beneficial effects probably by affecting three of the major integrating systems in the brain

Mesolimbic system

Mesocortical  system

Hypothalamus

Cause blockage mainly of postsynaptic dopaminergic (D2)  receptors and to smaller extent 5-HT receptors

Modify the function  of the  mesolimbic system
Reduce the incoming sensory stimuli by acting on the brainstem reticular formation

Pharmacological actions
On CNS
When chlorpromazine is given to patients with psychosis , it produces

Psychomotor slowing

Emotional quietening

Decreased initiative

Decreased anxiety

Phenothiazines do not have as analgesic effect

But they potentate the analgesic effect of morphine

They don’t have anticonvulsant effect
Behavioral effects

In normal subjects CPZ reduces motor activity, produces drowsiness and indifference to surroundings

In psychotic agitated patients, it reduce aggression , initiative and motor activity, relieves anxiety and brings about emotional quietening and drowsiness

It normalizes the sleep disturbances characteristic of psychoses


Other CNS actions


Cortex

CPZ  lowers seizure threshold and can precipitate convulsions in untreated epileptics


Hypothalamus

CPZ decreases gonadotrophin secretion and may result in amenorrhea in women
It increases the secretion of prolactin resulting ins galactorrhiea and gynaecomastia


Basal ganglia

CPZ  acts as a dopamine antagonist and therefore results in extra-pyramidal motor symptoms  ( drug induced parkinsonism)


Brainstem

Vasomotor reflexes are depressed leading to a  fall in BP


Anti-emetic action

CPZ  has a powerful anti emetic effect

These block the dopamine (DA) receptors in the CTZ

This effect is produced by depress  the chemoreceptor trigger zone

On ANS

The actions on the ANS are complex
CPZ is an alpha  adrenergic  blocker

The alpha blocking potency varies with each neuroleptic

CPZ also has ant cholinergic properties which leads to side effects like dryness of mouth, blurred vision, reduced sweating, decreased gastric motility, constipation and urinary retention

The degree of anti cholinergic activity also varies with each drug


CVS

CPZ produce hypotension due to alpha blockade action and reflex tachycardia

It also has a direct myocardiac depressant effect like guanidine

It also has anti- fibrillatory effect


Local anesthetic effect

These has local anesthetic properties but is not used for the purpose since in is an irritant


Kidney

CPZ depresses ADH secretion and has weak diuretic effects

Tolerance develops to the sedative and hypertensive actions while no tolerance is seen to the anti psychotic actions


On endocrine glands

These produces inhibition of ovulation,  amamenorrhea and lactation in females

In males, it produces loss of libido

These effect are produced by blocking  the action of dopamine on hypothalamus and pituitary

Other actions

Inhibition of hiccough

Skeletal muscle relaxant effect

Pharmacokinetics

It is well absorbed after oral and parenteral administration

It is highly protein bound

High concentration is found in the lungs, liver and adrenal glands

It is subjected to enterohepatic circulation

This increases its duration of action

The half life period is 20 to 24 hours and is therefore given once a day

It is metabolized in the liver and the metabolic products are excreted in urine s

Adverse reaction
CNS effects

Drowsiness, excitement, psychotic reactions, confusion and parkinsonism

ANS effects

Blurred vision, constipation, nasal stuffiness and urinary retention
These occur due to the ant cholinergic effects

CVS effects

Hypotension, palpitation and tachycardia

Hemopoietic effects

Agranulocytosis, thrombocytopenia and aplastic anemia

Endocrine effects

Gymaecomastia, lactation and menstrual disturbances


Hypersensinitivity reactions

Jaundice, agranulocytosis and skin rashes


Drug interactions

CPZ enhance the sedative effects of CNS depressants, alpha blockers and of ant cholinergic drugs

When combined with these groups of drugs , the effects may be additive

These inhibit the actions of dopamine agonists and Levo dopa

Dose

Chlorpromazine tablets and syrup- 25  to 1000mg  by mouth

Chlorpromazine injection-25 to 50 mg by intramuscular injection

Uses

These are given orally ( chlorpromazine 100 – 800mg)

In acute psychosis they may be given intramuscularly and response is seen in 24 hrs

While in chronic psychosis  it takes 2-3  weeks of treatment to demonstrate the beginning of obvious response

It is used in the treatment of major psychosis

It is used to control aggressiveness in children

It is used as ant emetic

CPZ can control intractable hic- cough

It is used in pre- anesthetic medication

It used in neuropsychiatry disorders such as Huntington’s  disease

Drug dependence
They are useful in the management of psychosis associated with chronic alcoholism but are contraindicated in acute withdrawal syndromes for fear of precipitating seizures

Haloperidol

This is a very potent drug, belonging go the class of  butyrophenones but with similar clinical effects as piperzine phenothiazines

It is more effective in highly agitated or manic patients and has less prominent  sedative and autonomic  effects than chlorpromazine

Mechanism of action

It blocks postsynaptic dopamine D1 and D2 receptors in the mesolimbic system and decreases the release of hypothalamic and hypophyseal hormones

It produces calmness and reduces aggressiveness with disappearance of hallucinations and delusions

Treatment

It is given orally in the dose of 1.5 to 7.5mg , there times day

It can also be given IM in the dose of 2-10 mg, repeated every hour up to  a total of 30 mg, in agitated and violent patients

Subcutaneous –Adult 5-15 mg given over 24 hrs

Depot injection preparation of haloperidol are also available

Interactions

Carbamazepine and rifampicin reduce plasma concentrations

The irreversible toxic encephalopathy has been reported in patients on lithium if they are given high doses of haloperidol

The other drugs of this series are trifluperidol  and droperidol which are used in combination with fentamyl for neuroleptanalgesia

Adverse drug reactions

Anxiety, drowsiness , depression , anorexia, hypotension and leucopenia  

Rauwolfia alkaloids

It is alkaloid obtained from a plant called Rauwolfia serpentine

In ancient Ayurvedic medicine, the extract of this plant has been claimed to be useful in cases of insomnia , insanity and snake bite

It is called serpentine because of the resemblances of the root to a snake

Mechanism of action

Reserpine is of great pharmacological interest because it produces depletion of endogenous catecholamine and 5-HTfron the brain and peripheral sites by interfering with amine storage

Such depletion can last for day or weeks

A single dose of 5 mg / kg body weight is sufficient to cause 90% reduction in brain nor adrenaline and 5-HT over a period of 10 days
This depletion of cerebral monoamines is believed to be responsible for its central actions
Pharmacological actions of reserpine

CNS
It has central antipsychotic action resembling those of phenothiazines

It differs from the latter compounds in that it has no antihistaminic, cholinergic blocking or direct adrenergic blocking effects

In man , it produces a similar calming effect as well as extra pyramidal action as those observed flowing chlorpromazine

It does not produce clouding of consciousness

Reserpine is less effective than phenothiazines  in t he treatment of schizophrenia

It may cause mental depression precipitating suicidal tendencies , hence it is no more used  as an antipsychotic drug

CVS
It is used as antihypertensive drug

Reserpine is less effective tam phenothiazines in the treatment of schizophrenia
But is  commonly used  as an antihypertensive drug


Clozapine

This antipsychotic drug, related to heterotricyclic compounds like imipramine , was synthesized in 1960

It was found to cause agranulocytosis and its use was abandoned

It has selective effects in the limbic, dopaminergic systems, its other actions include antiadrenergic , anti5-HT  and ant cholinergic actions

It differs from phenothiazines in that it causes fewer EPRs and does not cause hyperprolactinemia

It given orally, it produces antipsychotic effects similar to other standard neuroleptics

Its major advantage is that the drug improves not only the positive symptoms but also the negative symptoms such as emotional withdrawal, bunted affect, retardation and social withdrawal

It is started in the dose of 12.5  mg once daily and gradually increased to 200- 450 mg / day in divided doses  

Adverse reactions

These includes nausea, vomiting , sedation , hypotension , severe tachycardia , and confusion

Anti-depressant drugs
 These are the drugs used for the treatment of mental depression

They are also called as psycho analeptics or mood elevators


Classification of Anti-depressant drugs

1. Monoamine oxidase inhibitors

Meclobemide

Phenelzine

Isocarboxazid

Nialamide

11. Try cyclic compounds

Imipramine

Desipramine

Amitriptyline

Nortriptyline

111.  Selective Serotonin reuptake inhibitors
Fluoxetine

Citalopram

Escitalopram

Paroxetine

Sertaline

IV. Serotonin or nor epinephrine re-uptake inhibitors
Phenelzine
Tranyl -cypromine

1. Mono-amine oxidase inhibitors  (MAOI)

Monoamine oxidase  (MAO) is a mitochondrial enzyme found in nerve , liver and gut
In the neuron, MAO functions is to deaminate and inactivate any excess neurotransmitter molecules (nor epinephrine, dopamine and serotonin)  that may leak out of synaptic vesicles when the neuron is at test

The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presysaptic neuron and leak into the synaptic space

It enhance neuronal levels of nor-adrenaline , dopamine and 5-HT

This causes activation of nor- epinephrine and serotonin receptors and it may be responsible for the antidepressant action of these drugs

Two MAO inhibitors are currently available for treatment  of depression- Phenelzine and tranylcypromine

The use of MAO inhibitors is now limited due to the complicated dietary restrictions required of patients taking MAO inhibitors

Antidepressant actions develop slowly over week’s of treatment

Because of the side effects and drug interactions, MAOI are not the preferred antidepressants

 Mechanism of action

MAO inhibitors such as phenelzine form stable complex with enzyme, causing irreversible inactivation

These results in increased stores of nor epinephrine, serotonin and dopamine within the neuron  and subsequent diffusion of excess neurotransmitter into the synaptic space

These drugs inhibit the MAO in brain and as well as in  the peripher
 
Pharmacological actions

1.Behavior

In case o f mental depression, these compounds elevate the mood
The patient feels more energetic and  fresh

2. On CVS

No effect on heart or  circulation at normal dose

3. Potentiation of sympathomimetic amines

These compounds potentiate the action of symathomimitic amines like amphetamine and tyramine

These have a mild amphetamine like stimulant effect

They interact with many drugs and food

Pharmacokinetics

These drugs are will absorbed on oral administration

Antidepressant effects require two to four week of treatment

MAO inhibitors are metabolized and excreted rapidly in the urine

Adverse effects

Behavioral effects

Headache, excitement and disturbed sleep

CNS effects

Twitching, ataxia and tremors

ANS effects

Dry mouth, constipation and blurred vision

Hypertension

Tyramine is met abolished by the enzyme MAO

In presence of MAOI , tyramine is not metabolized

These leads to accumulation of tyramine

Tyramine produces rise in blood pressure by releasing nor adrenaline

Uses

MAO inhibitors are indicated for depressed patients who are un- responsive  or allergic to TCA or who experience strong anxiety

These drugs are also useful in the treatment of phobic state
s
MAO inhibitors also used in the treatment of a special subcategory of depression called atypical depression

Atypical depression is characterized by labile mood , rejection sensitivity and appetite disorders

Meclobemide

It is a MAO inhibitor

It is a reversible and selective inhibitor of the MAO isoenzyme inhibiting serotonin, nor epinephrine and dopamine metabolism result into an increase in the levels of neurotransmitters

Treatment

Adult -  Initially , 300 mg daily in divided doses taken alter food, increased up to 600 mg in 2 divided doses given after 3 days and continued for 8- 12 weeks

Drug interactions

May decreases t he effects of antihypertensive

Adverse drug interactions

Dizziness, headache, anxiety , agitation ,irritability y , constipation , dry mouth , sleep disturbances and visual disturbances

11. Tricyclic  antidepressants

These blocks nor epinephrine and serotonin uptake into the neuron

These drugs are voluble alternative for patients who do not respond to SSRIs

Mechanism of action

These are potent inhibitors of the neuronal re-uptake of nor epinephrine and serotonin into presynaptic nerve terminals

This produces increase in its concentration at the receptor sites

These contributes for the antidepressant action

TCAs also block serotonergic, alpha adrenergic ,histamine and muscarinic receptors


Pharmacological actions

1. Behavior

These elevate mood, improve mental alertness ,increase physical activity

The onset of the mood elevation is slow , requiring two weeks or longer

These drugs do not produce CNS stimulation or mood elevation in normal individuals

Physical and psychological dependence have been reported

The drugs can be used for prolonged treatment of depression without loss of effectiveness 

2. CVS

No effect at normal dose

But toxic doses may produce cardiac arrhythmias

3. ANS

Imipramine produces anti cholinergic effects like dry mouth, constipation , palpitation and blurred vision

ADME

Imipramine is well absorbed on oral administration

Because of their lipophilic nature ,they are widely distributed and readily penetrate into the CNS

This lipid solubility also causes these drugs to have long half lives – 4 – 17 hours for imipramine

These drugs are metabolized by the hepatic microsomal system and conjugated with glucuronic acid

The TCA are excreted as inactive metabolites via the kidney

It actions are mediated through desmethyl-imipramine  which is a metabolite product

Adverse reactions

CNS effects

Lethargy, headache and drowsiness

ANS effects

Dry mouth, constipation and tachycardia

CVS effects

Cardiac arrhythmias  and  hypotension

Allergic reactions

Skin rashes and photosensitivity

Uses

These are very effective  in treating severe major depression

Some panic disorders also respond to TCA

Imipramine has been used to control bed- wetting in children by causing contraction of the internal sphincter of the bladder

TCAs , particularly amitriptyline , have been used to treat chronic pain

Imipramine

It inhibits noradrenalin re- uptake and to a lesser extent that of serotonin

It is is relatively less sedating then amitriptyline and reduces REM sleep

It has few anticholinergic action and can PR interval and flatten or inverse T wave 

Treatment

Initially, 75 mg daily in divided doses increased gradually to 150—200 mg daily if necessary

300 mg daily given in severely depressed 

Drug interactions

Barbiturates reduces plasma levels thereby reducing antidepressant effect

Cimetidine elevates serum immpramine concentration  and consequently adverse effects causes drowsiness and impaired performance in combination with alcohol


Amitriptyline

Amitriptylin exerts its antidepressant action by blocking the neuronal re-uptake of Noradrenalin and serotonin

Treatment

Adults – 75 mg daily in divided doses or as a single dose at night , increased gradually , if necessary to 150 mg daily given in the late afternoon or evening

Alternatively 50- 100 mg a single dose at bedtime , increased by 25 – 50 mg

Child – 30 – 75 mg daily or in divided doses preferably at bedtime

Maximum dose

 Adult – 150mg daily

Treatment of severs depression

200- 300 mg daily , maximum dose 300 mg daily

Drug inter action

Potentates sedative effect of alcohol, antiparkinson agents and antipsychotic drugs increase risk of ant cholinergic effects

Reduced effect of anti hypertensive

Potentates hypertensive effects of sympthomimetics

Marked hyperpyrexia , convulsions and coma wit h MAOIs


Clomipramine

It is a potent inhibitor of serotonin re-uptake in t he brain

Significant antagonism at cholinergic and alpha receptors
Weak antagonism at dopamine receptors

It has also antidepressant , sedative and anticholinergic effects

Dose
 10 mg daily, gradually

250 mg daily given in severe cases

Doxepin

Doxepin inhibits serotonin  and noradrenalin re-uptake by the presynaptic neuronal membrane increasing its synaptic concentration in the CNS

 Dose

Initially 75 mg daily adjusted according to response, 300 mg daily in severely depressed patients
Pharmacological actions

1.Behavior

In case o f mental depression, these compounds elevate the mood
The patient feels more energetic and  fresh

2. On CVS

No effect on heart or  circulation at normal dose

3. Potentiation of sympathomimetic amines

These compounds potentiate the action of symathomimitic amines like amphetamine and tyramine

These have a mild amphetamine like stimulant effect

They interact with many drugs and food

Pharmacokinetics

These drugs are will absorbed on oral administration

Antidepressant effects require two to four week of treatment

MAO inhibitors are metabolized and excreted rapidly in the urine

Adverse effects

Behavioral effects

Headache, excitement and disturbed sleep

CNS effects

Twitching, ataxia and tremors

ANS effects

Dry mouth, constipation and blurred vision

Hypertension

Tyramine is met abolished by the enzyme MAO

In presence of MAOI , tyramine is not metabolized

These leads to accumulation of tyramine

Tyramine produces rise in blood pressure by releasing nor adrenaline

Uses

MAO inhibitors are indicated for depressed patients who are un- responsive  or allergic to TCA or who experience strong anxiety

These drugs are also useful in the treatment of phobic state
s
MAO inhibitors also used in the treatment of a special subcategory of depression called atypical depression

Atypical depression is characterized by labile mood , rejection sensitivity and appetite disorders

Meclobemide

It is a MAO inhibitor

It is a reversible and selective inhibitor of the MAO isoenzyme inhibiting serotonin, nor epinephrine and dopamine metabolism result into an increase in the levels of neurotransmitters

Treatment

Adult -  Initially , 300 mg daily in divided doses taken alter food, increased up to 600 mg in 2 divided doses given after 3 days and continued for 8- 12 weeks

Drug interactions

May decreases t he effects of antihypertensive

Adverse drug interactions

Dizziness, headache, anxiety , agitation ,irritability y , constipation , dry mouth , sleep disturbances and visual disturbances

11. Tricyclic  antidepressants

These blocks nor epinephrine and serotonin uptake into the neuron

These drugs are voluble alternative for patients who do not respond to SSRIs

Mechanism of action

These are potent inhibitors of the neuronal re-uptake of nor epinephrine and serotonin into presynaptic nerve terminals

This produces increase in its concentration at the receptor sites

These contributes for the antidepressant action

TCAs also block serotonergic, alpha adrenergic ,histamine and muscarinic receptors


Pharmacological actions

1. Behavior

These elevate mood, improve mental alertness ,increase physical activity

The onset of the mood elevation is slow , requiring two weeks or longer

These drugs do not produce CNS stimulation or mood elevation in normal individuals

Physical and psychological dependence have been reported

The drugs can be used for prolonged treatment of depression without loss of effectiveness 

2. CVS

No effect at normal dose

But toxic doses may produce cardiac arrhythmias

3. ANS

Imipramine produces anti cholinergic effects like dry mouth, constipation , palpitation and blurred vision

ADME

Imipramine is well absorbed on oral administration

Because of their lipophilic nature ,they are widely distributed and readily penetrate into the CNS

This lipid solubility also causes these drugs to have long half lives – 4 – 17 hours for imipramine

These drugs are metabolized by the hepatic microsomal system and conjugated with glucuronic acid

The TCA are excreted as inactive metabolites via the kidney

It actions are mediated through desmethyl-imipramine  which is a metabolite product

Adverse reactions

CNS effects

Lethargy, headache and drowsiness

ANS effects

Dry mouth, constipation and tachycardia

CVS effects

Cardiac arrhythmias  and  hypotension

Allergic reactions

Skin rashes and photosensitivity

Uses

These are very effective  in treating severe major depression

Some panic disorders also respond to TCA

Imipramine has been used to control bed- wetting in children by causing contraction of the internal sphincter of the bladder

TCAs , particularly amitriptyline , have been used to treat chronic pain

Imipramine

It inhibits noradrenalin re- uptake and to a lesser extent that of serotonin

It is is relatively less sedating then amitriptyline and reduces REM sleep

It has few anticholinergic action and can PR interval and flatten or inverse T wave 

Treatment

Initially, 75 mg daily in divided doses increased gradually to 150—200 mg daily if necessary

300 mg daily given in severely depressed 

Drug interactions

Barbiturates reduces plasma levels thereby reducing antidepressant effect

Cimetidine elevates serum immpramine concentration  and consequently adverse effects causes drowsiness and impaired performance in combination with alcohol


Amitriptyline

Amitriptylin exerts its antidepressant action by blocking the neuronal re-uptake of Noradrenalin and serotonin

Treatment

Adults – 75 mg daily in divided doses or as a single dose at night , increased gradually , if necessary to 150 mg daily given in the late afternoon or evening

Alternatively 50- 100 mg a single dose at bedtime , increased by 25 – 50 mg

Child – 30 – 75 mg daily or in divided doses preferably at bedtime

Maximum dose

 Adult – 150mg daily

Treatment of severs depression

200- 300 mg daily , maximum dose 300 mg daily

Drug inter action

Potentates sedative effect of alcohol, antiparkinson agents and antipsychotic drugs increase risk of ant cholinergic effects

Reduced effect of anti hypertensive

Potentates hypertensive effects of sympthomimetics

Marked hyperpyrexia , convulsions and coma wit h MAOIs


Clomipramine

It is a potent inhibitor of serotonin re-uptake in t he brain

Significant antagonism at cholinergic and alpha receptors
Weak antagonism at dopamine receptors

It has also antidepressant , sedative and anticholinergic effects

Dose

10 mg daily, gradually

250 mg daily given in severe cases

Doxepin

Doxepin inhibits serotonin  and noradrenalin re-uptake by the presynaptic neuronal membrane increasing its synaptic concentration in the CNS


Dose

Initially 75 mg daily adjusted according to response, 300 mg daily in severely depressed patients
Anti- manic drugs

The following drug are used in the treatment of manic disorder 

Lithium salts
Carbamazepine
Valproic acid

Lithium carbonates

It is a small monovalent cation

In 1949 it was found to be sedative in animals and to exert beneficial effects in manic patients

Mechanism of action

The mechanism of antimanic and mood stabilizing action of LI is not known
It has been proposed that

Lithium partly replaces body Na and is nearly equally distributed in and outside the cells ( contrast Na and K     ) ,  this may affect ionic fluxes across brain cells or modify the property of cellular membranes

Lithium has been found to decrease the release of Na and DA in t he brain of treated animals  without affecting 5 –HT release

This may correct imbalance in the turnover of brain monoamines

Pharmacological actions

On CNS

Lithium has practically  no acute effects in normal individuals as well as in MDI patients

It is neither sedative nor euphorient, but on prolonged administration,  It acts as a mood stabilser in bipolar disease

Given to patients in acute mania, it gradually suppresses the episode taking 1-2 weeks

The markedly reduced sleep time in manic patients is normalized


Other actions

Lithium inhibits action of ADH on distal tubules and causes a diabetes like state

It has some insulin like action on glucose metabolism

Leukocyte count is increased by lithium therapy

Lithium  reduces thyroxin synthesis by interfering with iodination of tyrosine 

Pharmacokinetics

Lithium is given orally and the ion is excreted by the kidney

It is neither protein bound nor metabolized

It first distributes in the extra cellular water and then gradually enters cells and slowly penetrates into the CNS , ultimately attaining a rather uniform distribution in total body water , apparent volume of distribution at steady- state  averages 0.8  L/kg

The lithium is handled by the kidney in much the same way as Na ,

Most of the filtered Lithium is reabsorbed in the proximal convoluted tubule

When Na is restricted, a larger fraction of filtered Na is reabsorbed , so is Li

After a single dose of li urinary excretion of rapid for 10- 12 hours followed by a much slower phase is 16- 30 hours

Renal clearance of lithium is 1/5  of creatinine clearance

On repeated medication steady-state  plasma concentrations achieved in 5-7 days

Levels are higher in older patients and in those with renal insufficiency

Peaks in plasma lithium level over and above the  steady-state level occur after every dose and produce episodes of toxicity if steady-state level if high or the dose is large

Divided daily  dosing in 2-4 portions is needed to avoid high peaks

Lithium is excreted  in sweat and saliva also salivary concentration is proportionate to serum concentration and may be used for noninvasive monitoring

Lithium is secreted in breast milk

Mothers on lithium should not breastfeed

Adverse reaction

Side effects are common but are mostly tolerable

Toxicity occurs at levels only marginally higher than therapeutic levels

Nausea, vomiting and mild diarrhea occur initially, can be minimized by starting at lower doses

Thirst and polyuria are experienced by most, some fluid retention may occur initially but clears later

Fine tremors and rarely seizures are seen even at therapeutic concentrations

CNS toxicity – coarse tremors, giddiness, ataxia, motor in coordination, mental confusion, slurred speech,

On long term use some patients develop renal diabetes  and goiter  has been reported in about 4 %

Interactions

Diuretics ( thiazide, furosemide0 by causing ) Na loss promote proximal tubular reabsorption of Na as well as lithium – plasma levels of lithium rise

Tetracycline’s , indomethacin and ACE inhibitors can also cause lithium retention

Lithium reduces presser response to NA

Lithium  tends to enhance insulin / sulfonylurea  induced hypoglycemia
Succinyl-choline and pancuronium have produced prolonged paralysis in lithium  treated patients

Haloperidol have been frequently used along with lithium without problem , sometimes , the combination of haloperidol and lithium produces marked tremor and rigidity

Dose

Lithium used as its carbonate salt because this is less hygroscopic and less gastric irritant than lithium chloride or other salts

It converted into chlorides in the stomach

It is generally stared at 600 mg/day and gradually increased to yields therapeutic plasma levels, mostly 600-1200 mg /day is required
 Carbamaepines

Actions

It reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potential in the epileptic focus and preventing their spread

ADME

It is absorbed slowly following oral administration

It enters the brain rapidly because of its high lipid solubility

It induces the drug metabolizing enzymes in the liver

The enhanced hepatic cytochrome p450 system activity also increases the metabolism of many drugs including other antiepileptic drugs

It is an inducer of the cytochromep450  isozyme  cyp3a4, which decrease                                                      the effects of drugs that are metabolized by his enzyme

Adverse effects

Chronic administration of carbamazepine can cause stupor, coma and respiratory depression

It also produces drowsiness, vertigo, ataxia, and blurred vision

The drug is irritating to the stomach and nausea and vomiting may occur

Drug interaction

The hepatic metabolism of carbamazepine is inhibited by several drugs

Toxic symptoms may arise if the dose is not adjusted

Therapeutic uses

It is effective in Temporal lobe epilepsy

Trigeminal neuralgia

Used in post hepatic pain

Hallucinogens

These are drugs which alter mood, behavior, thought and perception in a manner similar to that seen in psychosis

In appropriate doses these produce changes in visual, auditory perception,  in smell and  taste , broadly illusions and hallucinations

There will be alteration of the sense of time and space with personality changes

Memory is not affected
The drugs which possess their  actions  are cannabis, mescaline, LSE -25 , psilocybin , bufotenine and harmoline


Cannabis

It is obtained from cannabis indica or Indian hemp

Flowering tops  (ganja), the leaves  (bhang) , the resinous exudation  (Charas) or the whole drug ( Hashish)

In U.S.A. it is called as marihuana

Cannabinal  (chemically an alcohol)  a red syrapy oil is said to be the active principle

It produces hallucinations of time , space, euphoria ( sense of well being), imagination, mental exaltation, impulsive behavior, delirium ( confusion and excitement), mania
( mental disorder)

Cannabis is not useful therapeutically


Mescaline

It is an alkaloid obtained from a cactus

When given orally the drug produces sympathomimetic effects and visual hallucinations and a sense of floating in space

It also produces excitement ,  restlessness, change of mood and intelligence
It is used only for experimental purposes to produce psychotic states



LSD – 25  ( Lysergic acid diethylamide)

This is a derivative of ergot alkaloid, now being used in psychiatric research

It induces psychotic states in which repressed memories form the subconscious mind are brought of light

It stimulates emotional activity producing the sense of lightness and withdrawal from reality

It brings about personality change

It may be used in obsessional thoughts and anxiety conditions accompanied by mental tension

It is orally active in a  dose  of 25 micro gram

But it is widely misused for its hallucinogenic effects

The person become disoriented and his activities disorganized

It is noticed that it can induce chromosomal abnormalities and fetal malformation and possibly leukemia and hence it I withdrawn even form research

Other minor hallucinogens like bufetinine, psilocybin and harmolin produce similar psychic effects but not used therapeutically.

Hypnotics and sedatives ,Antianxiety drugs & Centrally acting muscle relaxants


Hypnotics are drugs which produce sleep resembling natural sleep


Sedatives are drugs which reduce excitement without producing sleep

They are 2 types of sleep
  1. Rapid Eye Movement (REM)
  2. Non Rapid Eye Movement (NREM)

  1. Rapid Eye Movement (REM)

Tension of the muscles can be studied

It can identified by Electromyogram

The REM comprise of 20- 25 % of sleep

It does not produce sleep spindles, eyeballs make rapid jerky movements and muscles are profoundly relaxed. This pattern is known as Rapid Eye Movement (REM) OR paradoxical sleep

Tachycardia and increase in blood pressure are seen in REM sleep also dreaming is there
      
  1. Non Rapid Eye Movement

It reveals eyeball movements

It can be identified by EOG – Electro Oculogram

It produces sleep spindles and prominent slow waves, the eye balls remain motionless and the muscles under the chain remain tense. This is known as Non – Rapid Eye Movement of orthodox sleep

The NREM sleep comprised 90% of sleep and during this period the growth hormones secretion are increased
      
 Qualitatively hypnotics and sedatives produce depression of CNS and the   
 difference between them is mainly quantitative

 Classification

1. Barbiturate derivatives
  2. Non – barbiturate derivatives

1 .Barbiturate derivatives

A. Long acting barbiturates   (8 -12 hours )

 Phenobarbitone

 Mephobarbitone

 Methylphenobarbitone

 Barbitone

B. Intermediate acting barbiturates

Amylobarbitone

Butobarbitone

Allobarbitone

Vinbarbitone

 C. Short acting barbiturates
 Pentobarbitone

Secobarbitone

Cyclobarbitone

Hepatobarbitone

D. Ultra short acting barbiturates

Thiobarbitone

Hexabarbitone

Methobarbitone

11. Non –barbiturate derivatives
 
A. Benzodiazepines

Diazepam

Oxazepam

 B.  Aldehydes

Chloral hydrate

Chloral formamide

Paraldehyde
 
C. Bromides

Potassium bromide

Sodium bromide

Ammonium bromide

 D. Alcohols

Ethyl alcohol

Tribromo-ehamol

Amylene hydrate
 
E. Piperidine derivatives
 Glutethimide

Methyprylon
 
Barbiturates
 Barbiturates o derivatives of barbituric acid which is obtained by condensation of urea  and malonic acid

Barbituric acid itself does not possess hypnotic activity but hypnotic activity is produced, if the hydrogen atoms at position 5 are replaced by alkyl or aryl groups

The barbiturates were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep

Today , they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance, drug metabolizing enzymes, physical dependence and 
severe withdrawal symptoms 

The barbiturates in severe doses produces coma
 
Mechanism action of barbiturates

The sedative – hypnotic action of the barbiturates is due to their interaction with GABA A receptors which enhances GABA nergic transmission

The binding site of distinct from that of the benzodiazepines

Barbiturates potentate GABA Acton on chloride entry into the neuron by prolonging the duration of the chloride channel openings

In addition , barbiturates can block excitatory glutamate receptors

Anesthetic concentration of pentobarbital also block high frequency sodium channels

All of these  molecular action lead to decreased neuronal activity

Pharmacological actions

On CNS

Barbiturates produce all degrees of   CNS depression like mild sedation, hypnosis and general anesthesia

Sleep

Barbiturate induced sleep resembles natural sleep

But it decreases the time spent on rapid-eye movement sleep, also there is hangover effect after awakening

Analgesic effect

Barbiturates do not relieve pain without producing unconsciousness

They enhance the analgesic effect of salicylates and Para-amino phenol derivatives

Anesthetic effect

Thiobarbiturates and some ultra short acting oxybarbriturates produce anesthesia on intravenous administration

Anti- consultant effect

Barbiturates like phenobarbitone which have a phenyl group at the 5 th carbon atom have anticonvulsant effect

Respiration

Respiration is not affected at sedative or hypnotic dose

Large dose administered intravenously may produce death due to central respiratory paralysis

GIT

Intestinal motility is not affected at a normal dose, but gastric secretion may be depressed

Uterus

Force and frequency of uterine contractions are depressed at toxic dose

Kidney

No effect at normal dose but anesthetic dose decreases urinary output due to decrease in
glomerular filtration and release of Ach

Liver

No effect at normal dose but anesthetic dose may produce hepatic dysfunction

Enzyme induction

Barbiturates induce P450 microsomal enzymes in the liver

Chronic barbiturate administration diminishes the action of many drugs that a    re dependent on P450 metabolism to reduce their concentration

ADME
Barbiturates can be administered  by oral and parenteral routes
They are distributed in all tissues and body fluids
They cross placental barrier and also are excreted in milk
 They are chiefly metabolized in the liver and to a small extent in kidney and brain
Excretion is through urine both in free form and as glucuronic acid conjugate


Adverse reaction
Intolerance like nausea, headache and diarrhea
Fetal respiratory depression if administered during labor
Drug automatism due to repeatedly taking the drug owing to forgetfulness
Tolerance because of increased inactivation in the liver
Dependence and withdrawal symptoms

Therapeutic uses
1. Sedation in case of anxiety or tension
2. Hypnosis to relieve insomnia
3. Anticonvulsant effect in case of tetanus or status epilepticus
4. Pre anesthetic medication and to produce basal anesthesia
5. Potentiation of analgesics like salicylates
6. In psychiatric practice and in neonatal jaundice

Phenobarbitone

Phenobaarbitone is a short acting barbiturate with sedative, hypnotic and anticonvulsant effects

It depresses sensory cortex, decreases motor activity , alters cerebella function and produces drowsiness, sedation and hypnosis

Its anticonvulsant property is exhibited at high doses

Dose

It is available in tab and injection

It is available in 30 , 60 and 100mg

Sedative dose  -  15 – 30mg  ( 3 – 4 times / day )

Hypnotic dose  - 100- 200 mg  (100 – 200 mg / day)

Phenobarbitone inj  - 200 mg  -  Hypnotic dose  - 60 – 200 mg

Drug interactions

Additive sedative effect with alcohol and other CNS depressants

Adverse drug reactions

Sedation, depression, confusion, headache ataxia, hypothermia and mood changes and impairment of memory

Benzodiazepines

These are very important class of hypnotics and sedatives because of their high therapeutic index

The important Benzodiazepines are
Diazepam
Flurazepam
Nitrazepam
Lorazepam
Oxazepam

Mechanism of action
The GABA  (Gamma amino butyric acid ) is acts as an inhibitory neurotransmitter in the body

It acts on GABA receptors

But the benzodiazepine receptor are associated with GABA receptors

These benzodiazepines  acts on GABA and  stimulate the GABA receptors , leading to increase in the GABA activity

GABA activating the chloride channels leading to increase in the Cl conductance and hence decrease firing of the regions

Benzodiazepines produce increase in pre-synaptic inhibition , decrease in turnover of 5HT, nor adrenaline and dopamine

These also posses GABA agonistic activity

Therapeutic uses

In anxiety and insomnia

As a pre-anesthetic medication

Treatment of epilepsy and seizure states or muscular relaxation in spastic conditions

In control of ethanol and sedative- hypnotic withdrawal symptoms

As diagnostic aid for treatment in psychiatry

Adverse effects
Drowsiness, confusion, impaired motor in co-ordination, tolerance and dependence to the less extent and reparatory depression

Chloral hydrate

Chloral hydrate is a trichlorinated derivative of acetaldehyde .

It is converted to the active metabolite , trichloroethanol, in the body

The drug is an effective sedative and hypnotic that induces sleep in about  thirty minutes and lasts about six hours

Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric distress

It also produces an unusual, unpleasant taste sensation

It synergizes with ethanol

It does not have the analgesic activity but may produce excitement and delirium in presence of pain

Adverse effects

Nausea, vomiting, gastric irritation, respiratory and vasomotor depression , myocardial depression and arrhythmia

Paraldehyde
It is nauseating and volatile, liquid hypnotic which is harmless and quick in Acton

It is more potent than the chloral hydrate  and polymer of acetaldehyde

During labor it causes analgesic effect but it can cross placenta and may delay respiration in new born

Higher doses may cause hypotension, respiratory  depression and coma

It can be used as anticonvulsant , hypnotic and basal anesthetic

It is absorbed thorough the oral and parental administration

It is excreted through the lungs with offensive smell

It reacts with plastic materials so cannot administer with the plastic syringes

Rectal administration cause irritation to mucosa of rectum an may cause ulceration

Ethyl alcohol

It has antianxiety and sedative effects , but its toxic potential outweighs its benefits

Alcoholism is a serious medical and social problem

Ethanol is a CNS depressant  producing sedation and ultimately hypnosis with increasing dosage

It is readily absorbed orally and has a volume of distribution close to that of total body water

It is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenate  and then to acetate by aldehyde dehydrogenate

Elimination is mostly through the kidney, but a fraction is excreted through the lungs

Ethanol synergizes wit h many other sedative agents and can produce severe CNS depression with antihistamines or barbiturates

Chronic consumption can lead to severe liver disease, gastritis and nutritional deficiencies

Cardiomyopathy is also a consequence of heavy drinking

The treatment of choice for alcohol withdrawal are the benzodiazepines

Carbamzepine is effective in treating convulsive episodes during withdrawal
 
Antianxiety drugs

Def
Antianxiety drugs (anxiolytics) are CNS depressants which control symptom of anxiety
They produce a calming effect in anxiety states

1. Benzodiazepines
Diazepam

Oxazepam

Lorazepam

Alprazolam


2. Azapirones

Buspirone

Gipirone

Benzodiazepines
These are the commonly used antianxiety drugs
They have anxiolytic, hypnotic, muscle relaxant and anticonvulsant actions
They are less toxic and addiction liability is very low

Classification
These are classified on the basis of duration of action   & therapeutic action

A. Classification on duration of action
  1. Ultra short acting BZDs
Half life – 2- 4 hrs,  Duration of action – less than 6 hrs
Ex – Triazolam,  Midazolam           
  1. Short acting BZDs
Half life – 10 – 15 hrs,  Duration of action – less than 6 hrs
Ex – Oxazepam, Temazepam          
  1. Intermediate BZDs
Half life – 20 – 30 hrs,  Duration of action – 8 – 10 hrs
Ex – Nitrazepam
  1. Long acting BZDs
Half life – 20 – 40 hrs,  Duration of action – More than 24 hrs
Ex – Diazepam , flurazepam , Clonazepam


B. Classification according to therapeutic uses

1. Anxiolytic benzodiazepines

     Diazepam, Oxazepam, Lorazepam, Alprazolam


2. Hypnotic benzodiazepines

    Nitrazepam, Temazepam, Estazolam

3. Antiepileptic benzodiazepines

     Clonazepam

4. Anesthetic benzodiazepines

      Midazolam

Mechanism of action

It is believed that these agents facilitate the effects of GABA receptor activation in the CNS

It potentates GABA ergic inhibition
Side effects
Sedation
Lethargy
Ataxia
Weight gain
Confusion
Tolerance
Dependence

Diazepam

It is an important benzodiazepine compound

Like all other benzodiazepines, it has a hypnotic, anxiolytic, muscle relaxant and anticonvulsant actions

It is quickly  absorbed on oral administration

Uses

Acute panic states

Anxiety associated with organic disease

Status epileptic us

Dose

2- 5 mg twice a day

Oxazepam

It is active metabolites of diazepam

This benzodiazepine is slowly absorbed on oral administration also

It also penetration slow

It has a short duration of action

So it is used mainly in short lasting anxiety states

Dis-advantages

It is short acting

It is not well absorbed


Dose

10 mg /day
 
Lorazepam

This benzodiazepine is slowly absorbed on oral administration

It also penetration in brain is slow

It has a short duration of action

So it is used mainly in short lasting anxiety states

Dose

1-4mg

Alprazolam

It is a recently introduce antianxiety drug

In addition to anxiolytic effect

It has a mood elevating action

It also produces less drowsiness

Use

Anxiety states associated with depression

Dose

0.25-1 mg three times daily


Meprobamate

The drug produces calmness In as individual

It reduces tension and hostility

Reactions of the patient to his environment become – congenial

Unlike phenothiazines it dies not abolish conditioned reflexes


Adverse reaction

Drowsiness
Angioneurotic edema and other r allergic manifestations
Blood dyscrasias


Disadvantages

Tolerance develops

IT produces drug

Dependence

Uses

Anxiety

Neurosis


Chlordiazapoxide

Though it is a benzodiazepine, its actions resemble barbiturates

It produces calmness

It also produces sedation

It produces skeletal muscle relaxation

It stimulates appetite

Adverse reaction

Drowsiness, lethargy and ataxia

Hypotension is produce in few

Disadvantages

Tolerance develops

It induces physical dependence , withdrawal symptoms are produced on its stoppage


Use

Anxiety and neurosis

It is used to suppress withdrawal symptoms of alcohol

As preanaesthestic medication

Buspirones

It is new antianxiety drug

It does not have sedative, hypnotic, muscle relaxant and anticonvulsant effects as
produced by benzodiazepines

It has a slow action and the effect is delayed for even two weeks


Mechanism of action

It acts by stimulating presynaptic 5-HT 1A auto receptors

Use

Mild to moderate anxiety

Dose

10-30 mg daily is divided doses 

Flumazinil

It is a benzodiazepine antagonist

It binds competitively with benzodiazepine receptors and blocks many of the pharmacological actions of benzodiazepines

Use

To reverse benzodiazepine anesthesia

In Benzodiazepine overdose

Hepatic coma and alcohol intoxication

Centrally acting muscle relaxants

Skeletal muscle relaxation without altering consciousness or normal voluntary movement is necessary during unwanted muscular spasms and rigidity and during operative procedures

The classes of drugs which can be used fro skeletal muscle relaxation are centrally acting drugs and drugs acting peripherally at neuromuscular junction

1. Mephenesin group

           Mephenesin
           Carisoprodol
           Chlorzoxazone
           Chlormezamone
           Methocarbamol

2 .Benzodiazepines

           Diazepam and others

3. GABA derivative
       
         Baclofen

4. Central alpha 2 agonists

        Tizanidine

Mepaenesin

It is the first centrally acting muscle relaxant which was introduced in 1946 still being widely used today

It relaxes normal and spastic skeletal muscles without interfering within neuro-muscular transmission

In moderate dose it reduces muscle tone and motor activities

But large doses produce hypotension, respiratory paralyses and death

The drug is will absorbed orally and parent rally ,but duration of action is short

It is used to treat acute spasm of skeletal muscle in tetanus and status epileptic us

It is used to produce muscular relaxation during operative procedures

Use to reduce agitation in chronic alcoholism an to relieve muscular rigidity and tremors in parkinsonism

Dose

Orally 1 gram to 3 grams

Parentally 100mg to 1 gram

Mephenesin carbamate an ester of mephanesin has a longer duration of action and hence is preferred

Dose – 1 to 1.2 gram per day orally

Methocarbamol

This chemically elated to mephenesin carbamate

It acts both as muscle relaxant and sedative

It is orally active with a longer duration of action and milder side effects

Uses

Same as mephenesin

Dose

0.5 grams per day orally

It can also be given by I.M or  I.V route

Carisoprodol

It is chemically related  to meprobamate

It produces muscle relaxation and sedative effects

It is used  in cerebral palsy to produce muscular relaxation

Unwanted side effects are drowsiness, vertigo, weakness and allergic reactions on skin

Dose 
350 mg oral


Metaxalone

Dose -   0 3.2 rams per day in divided doses

Serious side effects are leucopenia and jaundice

Muscle relaxants  are contra-indicated in pregnant women , in the presence of renal damage and myasthenia gravis

Muscle relaxants acting at neuromuscular junction

The contraction of  skeletal muscle is initiated by acetyl choline at the neuromuscular junction

Acetyl choline acts on the receptor of the muscle producing  contraction

But there are drugs which block the action f acetyl choline on skeletal muscle receptors thereby producing muscle relaxation

They are of two types namely

1. Competitive blockers

2. Depolarization blockers 

1. Competitive Blockers

The drugs which act by this mechanism are d-tubocurarine and gallamine

They compete with the acetylcholine to reach the muscle receptors

D-Tubocurarine
This is the dextro rotatory alkaloid obtained from the strychnos species

Curare was mainly used as an arrow poison in South America

It competes with acetyl choline to reach the receptors and thus blocks the action of acetylcholine at the neuromuscular junction and produces muscle  relaxation

It is inactive orally, but is active parent rally

The drug is given intravenously for muscle relaxation during operative procedures

Dose  --  6 to 10 mg given with general anesthetic
Disadvantage   -  It is that it causes release of histamines from the tissues 
Gallamine

It is a synthetics quaternary ammonium compound with curare like action

It also acts as a skeletal muscle relaxant by competitive blockade of acetylcholine

But is less potent than d – tubocurarine
It does not release histamine
It is not active orally
Hence given parent rally

It is also used to produce muscular relaxation during operative procedures

Dose

100 mg by I.V injection

Depolarization blockers

Here the drugs act by depolarizing the receptor motor end plate of the muscle which becomes resistance to further stimulation

The drug which stimulation

The drug which acts by this process and relaxing skeletal muscles is succinyl chloride

It has very short duration of action

Its action can be enhanced by anti-choline  esterasis like neostigmine

It does not release histamine

It is used in anesthesiology to produce muscle relaxation by continuous I. V infusion

Other drugs which act this process is decamethonoum