antidepressants and anxiolytics

VIGNAN PHARMACY COLLEGE,VADLAMUDI,522213.

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Presented by: Under guidence of: D.Gnana Bhaskar K.V.Santhosh kumar 12AB1R0015 (assistant professor) Dept. of medicinal chemistryVIGNAN PHARMACY

COLLEGE,VADLAMUDI,522213,GUNTUR.(DT),APAFFILATED TO JNTUKAPPROVED BY AICTE


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A CLASS OF PSYCHOTROPICS

ANTIDEPRESSENTS&ANXIOLYTICS


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OVERALL CONTENT VIEW

DEPRESSION

&ANXIETY

1. DEFINITION2.SYMPTOMS3.PATHOPHYSIOLOGY4.TYPES5.TREATMENT

OF


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:DEFINITION:(3)

In Depressed states one who feels exhausted, wrothless, hopeless that immobilizes any kind of people neither poor or rich.it also interfers with the persn’s ability to do daily activities.It mostly comman1 in 4women&1in 10 men

:SYMPTOMS:

sadness Empty moods

Sucidal thoughts

Poor self esteem


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OTHER SYMPTOMS INCLUDE• persistently sad, anxious, or empty moods

• loss of pleasure in usual activities (anhedonia)

• feelings of helplessness, guilt, or worthlessness

• crying, hopelessness, or persistent pessimism

• fatigue or decreased energy

• loss of memory, concentration, or decision-making capability

• restlessness, irritability

• sleep disturbances

• change in appetite or weight

• physical symptoms that defy diagnosis and do not respond to treatment (especially pain and gastrointestinal complaints)

• thoughts of suicide or death, or suicide attempts

• poor self-image or self-esteem (as illustrated, for example, by verbal self-reproach)


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PATHOPHYSIOLOGY(3)

• Different theories are there to explain about various causes of the depression During the late 1960’s a Swiss psychiatrist, proposed that “it is important to select a right anti depressant for the right patient ”. because vast no of classes are available it should properly selected. For that he differentiated TCAs based on whether they possessed ability to sedate or stimulte.

• Eg :sedate :triimpramine, stimulate : nortriptyline1. Mono amine hypothesis2. Receptor sensitivity hypothesis3. Changes in HPA4. Balance between neurotransmitters


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MONO AMINE HYPOTHESIS (NEUROCHEMICAL THEORY)

ANTIDEPRESSENTS

ACT TO CORRECT THOSE DEFFICIENCIES

Deffiiency of 5HT/NE amines likeSERITONIN NOREPINEPHRINE

The mono amine hypothesis proposes thatDepression results from


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CATECHOL AMINE HYPOTHESIS

Decreased concentration ofNeurotransmitters at the synaptic cleft


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RECEPTOR SENSITIVITY HYPOTHESIS• It proposes that it is not the matter involved in the level of

norepinephrine & seritonin in the synapse. the matter involved is sensitivity of post synaptic receptors to the neurotransmitters.

• This is important theory that helps to know about the long delay between administration Of anti depressant drug &its clinical response.

• To desensitize & to increase the no of receptors presence :chronic administration of antidepressant drugs in an gradual increasing concentration there by due to their actions neurotransmitters concentrations will increase in synaptic cleft.it causes post synaptic activity aswell as down regulation of neurotransmitters .

• Supersensitivity and up-regulation of post-synaptic receptors leads to depression

• Suicidal and depressed patients have increased 5HT-α2 receptors


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No of receptors involving

Receptorssensitivity

Optimum good

activity

Not only levels of

neurotransmiters

&


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CHANGES IN HYPO PITUTORY ADRENAL AXIS(HPA)• It suggests that changes in HPA axis can influence the levels of NE, 5HT, released by

nerve cells in the brain there by the activity also get influenced.

NE,5HT,CORTISOL, HYDROCORTISOL

ADH

Enoorphin RF

Stress events


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BALANCE BETWEEN NOR EPINEPHRINE• This theory emphasizing that importance of balance between 5HT&NE in regulating

absolute levels of these neurotransmitters at the synaptic cleft.

• Ex. : If 5HT levels are too low the balanced NE system is lost there by disorders can be happen .

• COGNITIVE SLOWING• HYPER SOMNIA

• DECREASED CONCENTRATION

• ANXIETY• PANIC• PHOBIA• OCD

5HT NE

DEPRESSED

MOOD

DOPAMINE


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TYPES OF DEPRESSION

DEPRESSION

BIPOLAR DISORDER

BIPOLAR1

BIPOLAR2MAJOR

DEPRESSIVE DISORDER

CHRONIC DEPRESSION DYSTHMIA

SEASANOL DEPRESSION


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MAJOR DEPRESSIVE DISORDER(3)

defn.

• Also known as unipolar depression• It changes the brain function where those who persistently think they

are less self esteem themselves among the world

about

• It may also get inheritated for further generations• It lasts for 2 years or more

Psychotherapymedication

• The first line treatment drug is SSRIs• They termed as first drug among 50 drugs prescribed


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CHRONIC ANXIETY(DYSTHIMIA)

Characterized by chronic symptoms

Low self esteem

Anti depressantspsychotherapy

• One from functioning well

• Feeling less value about them selvs

• Just pass through situation without involvement


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BIPOLAR DISORDER

Bipolar1Manichighs

Bipolar2Hypomanic

lows

This is generally because of lows and highs abnormalities of neurotransmitters levels which Causes both depression mania.

This is because of problematic disruption of signaling pathways in hypothalmic pitutory regionGeneral drugs used Lithium, Carbamazepine,Topiramide


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OTHER TYPES OF DEPRESSIVE DISORDERS

occurance

• This disorder involves symptoms of depression during fall&winter season

how

• It is an adjustment disorder with depressed mood • When a person lost his job when the situation location repeat he will

get this sort of depression

additionals.

• Stress at home, work,• It may persists for 6months.


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TREATMENT(1)(7)(4)(5)

Treatment

psychotherapy

medication

SSRI

MAOIs

TCAs/NSRIs

Electro convulsent therapy SNRIs

AAD/DNRIs


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MEDICATION• Antidepressants:

• SSRIs : fluoxetine ,sertraline, citalopram, escitalopram, paroxetine.

• SNRIs : duloxetine, venalfaxine.

• AAD/DNRI : Bupropion, mitrazepine, nefazodone, trazodone.

• TCAs/NSRIs:Amitryptiline,cloimipramine,doxepine,nortryptyline,protryptyline

• Mood stabilizers

PSYCHOTHERAPY(7)COGNITIVEMODELBEHAVIOURAL ACTIVATIONINTER PERSANOL MODEL


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SELECTIVE SEROTONIN REUPTAKE INHIBITOR -SSRIMechanism of actionMost commonly prescribed classCurrent drugsSide effects

Mechanism of action

• They are having 300-3000-fold grater activity towards seritonin transporter rather than nor epinphrine transporter

• They block the reuptake of serotonin from reuptaking, leading to increased concn of serotonin in the synaptic cleft.

• They take at least 2 weeks toproduce significant effects.


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Exact mechanism remains uncertain Ser-438 residue in the human serotonin

transporter (hSERT) appears to be a determining factor in SSRI potency

Antidepressants interact directly with hSERT


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SSRIS IN THE MARKET• citalopram (Celexa)

• dapoxetine (Priligy)

• escitalopram (Lexapro)

• fluoxetine (Prozac)

• fluvoxamine (Luvox)

• paroxetine (Paxil)

• sertraline (Zoloft)

• zimelidine (Zelmid) (discontinued)

• indalpine (Upstene) (discontinued)

fluoxetine

sertraline


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SYNTHESIS OF FLUOXETINE


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SIDE EFFECTS OF SSRIS• Anhedonia• Apathy• Nausea/vomiting• Drowsiness or somnolence• Headache• Bruxism (involuntarily grinding of the teeth)• Extremely vivid and strange dreams• Dizziness• Fatigue• Changes in sexual behavior• Suicidal thoughtsMany disappear within 4 weeks (adaption phase)• Side effects more manageable compared to MAOIs and TCAs• Sexual side effects are common• SSRI cessation syndrome

• Brain zaps• Sexual dysfunction


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THERAPEUTIC USES:Primary indication for depressionThey effective as TCAsOther psychotic disorders also respond for this classThey are also used for GAD, OCD.

PHARMACOKINETICS:All are well absorbed through oral routePeak concentration reach with in 8hoursHalf life16 hr

Caution:Fluoxetine sertraline are potent inhibitors of P450 enzyme system which is responsible for the elimination of TCAs Neuroleptics.Hence they effect the metabolism of other drugs


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TRI CYCLIC ANTI DEPRESSANTS-TCAHistory

ImipramineCurrent DrugsMechanism of ActionSide Effects

TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake

TCAs also allow for the downregulation of post-synaptic receptors by blocking the receptors.

All TCAs and SSRIs contain an essential amino group that appears to interact with Asp-98 in hSERT


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ACTIONS• TCAs elevate mood ,physical activity,improve mental alternesss

• Reduce morbid pre occupation in 50TO 70% of individuals.

• Treat moderate to severe major depression,some panic attacks also respond to this.

PHARMACOKINETICS

• Well absorbed orally because of its lipophilic nature• They widely distributed into CNS.• Dose adjustment done by patient response and plasma levels

Precaution

• Caution in manic depressive patients• 5-6doses of imipramine a lethal dose


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TCA ON MARKET& NEWER ONES• Amitriptyline

• Desipramine (Norpramin)

• Doxepin (Sinequan)

• Imipramine (Tofranil, Tofranil-PM) bed wetting in children

• Nortriptyline (Pamelor) migraine

• Protriptyline (Vivactil)

• Trimipramine (Surmontil)


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SYNTHESIS OF DOXEPIN


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SIDE EFFECT& ADVERSE REACTIONS• Muscarinic M1 receptor antagonism - anticholinergic effects including dry mouth,

blurred vision, constipation, urinary retention and impotence

• Histamine H1 receptor antagonism - sedation and weight gain

• Adrenergic α receptor antagonism - postural hypotension

• Direct membrane effects - reduced seizure threshold, arrhythmia

• Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety )

• Nonselectivity results in greater side effects

• TCAs can also lead to cardiotoxicity

• Increased LDH leakage

• Slow cardiac conduction

• High potency can lead to mania

• Contraindicated with persons with bipolar disorder or manic depression


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MAO INHIBITORS• MAO catalyze deamination of intracellular monoamines

• MAO-A oxidizes epinephrine, norepinephrine, serotonin

• MAO-B oxidizes phenylethylamine

• Both oxidize dopamine nonpreferentially

• MAO transporters reuptake extracellular monoamine


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• They are mitochondrial enzymes pesent in gut&liver tissues of neurons.• They act as saftey valves.• They oxidatively de aminate exessive neurotransmitters present at synaptoc cleft.• Mao inhibitors irreversibly bind to this enzyme and maintain the concentrtion normal.

amines

metabolise


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CURRENT DRUGS

• MAO Inhibitors (nonselective)

• Phenelzine (Nardil)

• Tranylcypromine (Parnate)

• Isocarboxazid (Marplan)

• MAO-B Inhibitors (selective for MAO-B)

• Selegiline (Emsam)

isoniazidiproniazid


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MECHANISM OF ACTION

• MAO contains a cysteinyl-linked flavin• MAOIs covalently bind to N-5 of the flavin residue of the enzyme

• Most MAO inhibitors forms an irreveresible complex with the enzyme.• This results in increase in stores of NE,5HT&dopamine• They not only bind MAO in brain but also in liver &gut• It shows that they are highly prone to drug-food interactions


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SIDE EFFECTS• Side effects have put MAOIs in the second or third line of defense despite superior

efficacy

• MAO-A inhibitors interfere with breakdown of tyramine

• High tyramine levels cause hypertensive crisis (the “cheese effect”)

• Can be controlled with restricted diet

• MAOIs interact with certain drugs

• Serotonin syndrome (muscle rigidity, fever, seizures)

• Pain medications and SSRIs must be avoided


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SERITONIN NOR EPINEPHRINR RE UPTAKE INHIBITORS- SNRI• It inhibit the re uptake of both NE&5HT

• They are ineffective in relieving pains

• Inhibitor of seritonin mostly then NE&DA

• Side effect are nausea sedation,insomnia.

venalfaxine

• It is also same inhibition effect

• Not prescribed in renal&hepatic failure patients.

duloxetine


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ATYPICAL ANTIDEPRESSENTS• They are mixed group of agents not much effective than others but side

effective profile is different.

• Bupropion: weak reuptaking inhibitor.it have short half life.used for cessation of smoking

• Mitrazapine :enhances the transmission of neurotransmitters.it have sedative property.

• Nefazodone,trazodone:they act by blocking post synaptic autoreceptors.

• nefazodone:pripism trazodone:hepatotoxicity


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PRIORITIES

• Based on:acceptance

SSRITCA

MAO

BASED ON SIDE EFFECTS:

SSRIMAO

TCA

BASED ON DURATION OF ACTION

ssri

mao

tca

ANXIETY-ANNXIOLYTICS


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DEFINITION• It is an adaptive response that prepares a person appropriately to the threatning situation

• Where its over response causes a maladaptive response which is inappropriate to the situation caused by psychological distress

• It interferes with the persons ability to do daily activities morever viscral oegan disfunction

difference

Anxiety required to face the threatning

Over responsive to the situation

Chronic: visceral organ disfunction


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SYMPTOMS

Common Emotional Symptoms of anxiety

• irrational and excessive fear and worry• Irritability • Restlessness • Trouble concentrating • Feeling tense

Common Physical Symptoms of Anxiety

SweatingTachycardia

Stomach upsetShortness of breath

Frequent urination or diarrhea Sleep disturbances (Insomnia)

Fatigue


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PATHOPHYSIOLOGYo Neurotransmitters like GABA, noradrenaline, serotonin abnormalities – anxiety.

o Amygdala, temporal lobe, hippocampus and hypothalamus - involved in anxeity.

1. Nor-adrenaline theory2. Serotonin theory3. GABA receptor theory


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GABA RECEPTOR THEORY


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SERITONIN THEORY


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NOR ADRENALINE THEORY

• In response to threat or fearful situations, the Locus cerulus serves as an alarm center, activating NE release and stimulating the sympathetic and parasympathetic nervous systems.

• In response to threat or fearful situations, the Locus cerulus serves as an alarm center, activating NE release and stimulating the sympathetic and parasympathetic nervous systems.


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TYPES OF ANXIETY

ANXIETY

GAD SAD OCD PHOBIAS

ACUTE ANXIETYPANIC DISORDER


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GAD:GENARALIZED ANXIETY• It is chronic and fills a person’s day with exaggerated worry and tension, even though there is little or

nothing to provoke it, associated with worrying excessively about health, money, family, school or work. Concentration and sleep problems are also common.

• COGNITIVE SYMPTOMS

• Excessive Anxiety

• Worries that are difficult to control

• Poor concentration or mind going blank

•

• PHYSICAL SYMPTOMS

• Sleep disturbance

• Irritability

• Restlessness

•


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PANIC DISORDER• Unexpected panic attacks associated with physiological symptoms of autonomic nervous system without any

warning or apparent reason.

• They can’t predict when an attack will occur, and many develop intense anxiety between episodes, worrying when and where the next one will occur.

• Symptoms include Attacks usually last no more than about 10 minutes.

• Symptoms

• Intensive fear

• Phobias

• Dizziness

• Racing heart

• Perspiring

• Shortness of breath

• Tingling hands

• Fear of dying or going crazy


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SOCIAL ANXIETY DISORDER• Characterized by an intense, irrational, persistant fear of situations, usually social or

performance situations, where risk of embarrassment is present. It can disrupt normal life, interfering with school, work or social relationships.

• Physical symptoms often accompany the anxious feelings.

• Blushing

• Profuse sweating

• Trembling

• Nausea

• Shortness of breath

• Racing heart

• Difficulty talking


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POST TRAUMATIC STRESS DISORDER• Develops subsequent to experiencing or witnessing a traumatic event

• Symptoms (lasting at least 4-6 weeks )

Flash-backs

Disturbing memories

Nightmares

Intrusive images


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PHOBIAS-SPECIFIC DISORDERS Is an intense fear of something that posses little or no actual danger of a object

or situation. Some of the more common specific phobias are Centered around closed-in places Heights Escalators Tunnels Water Flying dogs Injuries involving blood Injection Insects


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OBSESSIVE COMPULSIVE DISORDERS

Obsessions (recurrent, intrusive and generally distressing thoughts, images or feelings).

Compulsions(repetitive,ritualistic behaviors aimed to alleviate obsessions)


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TRETMENT ANXIOLYTICS+ANTIDEPRESSANTS+OTHERS

• Benzodiazepines ( BDZ ).

• 5HT1A agonists.

• 5HT reuptake inhibitors.

• Antidepressants

• beta-adrenergic blockers

• MAO inhibitors

•


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BENZODIAZEPINES• Short acting: (3-5 hours): triazolam

• - Intermediate: (6-24 hours)

• Alprazolam

• Lorazepam

• Oxazepam

• Estazolam

• Temazepam

•

• - Long acting: ( 24-72 hours)

• Clonazepam

• Chlordiazepoxide

• Diazepam

• Flurazepam


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MECHANISM OF ACTIONMechanism of Action Benzodiazepines act by binding to BZ receptors in the brain enhance GABA action on brain chloride channels opening chloride influx to the cell hyper- polarization inhibition of brain.


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SYNTHESIS OF SOME BENZODIAZEPINES


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PHRMACOLOGICAL ACTIONS•Anxiolytic action.

• Depression of cognitive and psychomotor function

• Sedative & hypnotic actions

• Anterograde amnesia.

• Minimal depressant effects on

Cardiovascular system

• Respiratory system

• Some have anticonvulsant effect:

• clonazepam, diazepam

• Treatment of epilepsy

• Diazepam – Lorazepam

• In anesthesia

• Preanesthetic medication (diazepam).

• Induction of anesthesia (Midazolam, IV)

Therapeutic Uses

Anxiety disorders: short term relief of severe anxiety

General anxiety disorderObsessive compulsive disorder

Panic attack with depression Alprazolam (antidepressant effect)

Sleep disorders (Insomnia).

Triazolam, Lorazepam, Flurazepam


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ADR

• Adverse Effects

• Ataxia (motor incoordination)• Cognitive impairment.• Hangover: (drowsiness, confusion) • Tolerance & dependence• Risk of withdrawal symptoms• Rebound Insomnia, anorexia, anxiety, agitation, tremors and

convulsion.

ExamplesCNS

depressants

Alcohol & Antihistaminics

of effect of benzodiazepines

Cytochrome P450 (CYT P450) inhibitors

Cimetidine & Erythromycin

t ½ of benzodiazepines

CYT P450

inducers

Phenytoin & Rifampicin

t 1/2 of benzodiazepines


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BARBITURATES

It was first isolated1864 by adolf Von bayerIt shows diverse effects from small change to obvious effects like sedation,general anesthesia

MechanismThey bind o allosteric site of GABA a receptors makes it easier to openAltering structure of ion channelmaking it easier to open

Short acting:thipental secobarbitrlIntermediate:amobarbital,hexobarbitalLong acting:phenobarbital,mephobarbital


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SYNTHESIS OF PHENO BARBITAL

Therpeutic uses:AnesthesiaAnti cconvulsant

Adr:Droowsiness impaired concentrationTirednessThey induce p450 so sow half life


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TCATricyclic AntidepressantsDoxepin- imipramine• act by reducing uptake of 5HT & NA.• Used for anxiety especially associated with depression.• Effective for panic attacks.• Delayed onset of action (weeks).• dry mouth, postural hypotension, sexual dysfunction, weight gain.

)

Fluoxetine acts by blocking uptake of 5HT

Orally Delayed onset of action (weeks).

Used for panic disorder – OCD depression- Generalized anxiety disorders - phobia.

Side Effects:Weight gain, sexual dysfunction, dry mouth

ssri

MONOAMINE OXIDASE INHIBITORSPhenelzine

Acts by blocking the action of MAO enzymes.Used for panic attacks and phobia.Require dietary restrictionAvoid wine, beer, fermented foods as old cheese that contain tyramine.Side effectsDry mouth, constipation, diarrhea, restlessness, dizziness.

mao

antidepressants and anxiolytics

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