- DR. SRIRAM.R

OVERVIEW OF PHARMACOTHERAPY

Clonidine and Guanfacine MOA - Stimulation of alpha2-adrenergic receptors reduces the firing

rate of noradrenergic neurons and of plasma concentrations of norepinephrine

Effective in reducing the autonomic symptoms of rapid opioid withdrawal

Reduce the frequency and severity of tics and used in Tourettes syndrome

Clonidine or guanfacine can be combined with methylphenidate (Ritalin) or amphetamine to treat hyperactivity and inattentiveness

Acute exacerbations of PTSD Anxiety disorders (panic disorder, phobias, obsessive-compulsive

disorder, and generalized anxiety disorder) and mania, in which it may be synergistic with lithium (Eskalith) or carbamazepine (Tegretol)

ALPHA-2 AGONISTS

BETA BLOCKERS

The beta-receptor antagonists are beneficial for lithium-induced postural tremor and other medication-induced postural tremors for example, those induced by tricyclic drugs and valproate (Depakene)

Neuroleptic-Induced Acute Akathisia Effective in reducing the number of aggressive and

violent outbursts in persons with impulse disorders, schizophrenia, and aggression associated with brain injuries, such as trauma, tumors, anoxic injury, encephalitis, alcohol dependence, and degenerative disorders (e.g., Huntington's disease)

Propranolol is reported to be useful as an adjuvant to benzodiazepines, but not as a sole agent in the treatment of alcohol withdrawal

Pindolol has been used to augment and hasten the antidepressant effects of SSRIs

Used in some cases of stuttering

ANTICHOLINERGICS

The primary indication for the use of anticholinergics in psychiatric practice is for the treatment of neuroleptic-induced parkinsonism, characterized by tremor, rigidity, cogwheeling, bradykinesia, sialorrhea, stooped posture, and festination

Another indication is for the treatment of neuroleptic-induced acute dystonia, which is most common in young men

AMANTADINE

It is the organic compound 1-adamantylamine or 1-aminoadamantane

The primary indication for amantadine use in psychiatry is to treat extrapyramidal signs and symptoms, such as parkinsonism, akinesia, and so-called rabbit syndrome

(SSRI)-associated side effects, such as lethargy, fatigue, anorgasmia, and ejaculatory inhibition

Treatment of parkinsonism of all causes, including idiopathic parkinsonism

ANTICONVULSANTS

Gabapentin is used as a hypnotic agent, Anxiolytic – Panic attacks and Social anxiety, Decreases alcohol craving, used in alcoholics with liver disease,Reduces alcohol intake in BPAD patients, Used in pain syndromes and post herpetic neuralgia

Pregabalin has been found to be of benefit to some patients with generalized anxiety disorder

Topiramate has been shown to benefit patients with primary alcoholism and posttraumatic stress disorder.

Topiramate may reduce the frequency of cutting and other forms of self-mutilating behavior in patients with borderline personality disorder. It is effective in treating neuropathic pain and migraine and is also highly effective in treating binge-eating disorder.

Tiagabine is occasionally used as an anxiolytic or hypnotic agent in patients who have not responded to, or tolerated, standard treatments

Zonisamide is sometimes used as an alternative treatment for acute mania and as a weight loss agent for drug-induced weight gain

Levetiracetam has been used to treat acute mania, as add-on therapy to antidepressants to prevent the emergence of mania or cycling, and as an anxiolytic.

ANTIHISTAMINES

Antihistamines are useful as a treatment for neuroleptic-induced parkinsonism, neuroleptic-induced acute dystonia, and neuroleptic-induced akathisia

The antihistamines are relatively safe hypnotics, but they are not superior to the benzodiazepines

Cyproheptadine is sometimes used to treat delayed orgasms due to SSRI, anorexia nervosa, reduces recurrent nightmares and has antiserotonergic activity

BARBITURATES AND SIMILAR DRUGS

Methohexital (Brevital) is commonly used as an anesthetic agent for electroconvulsive therapy (ECT). It has lower cardiac risks than other barbiturate anesthetics

Phenobarbital – GTCS and partial seizures Narcoanalysis - Amobarbital (Amytal) has been used

historically as a diagnostic aid in a number of clinical conditions, including conversion reactions, catatonia, hysterical stupor, and unexplained muteness, and to differentiate stupor of depression, schizophrenia, and structural brain lesions.

Paraldehyde is a cyclic ether, first used in 1882 as a hypnotic, little place in current psychopharmacology

Meprobamate, a carbamate, was introduced shortly before the benzodiazepines, specifically to treat anxiety. It is also used for muscle relaxant effects

Chloral hydrate is a hypnotic agent rarely used in psychiatry

Diazepam, chlordiazepoxide, clonazepam (Klonopin), clorazepate, flurazepam (Dalmane), prazepam (Centrax), quazepam (Doral), and halazepam (Paxipam) have plasma half-lives of 30 to more than 100 hours and, therefore, are the longest-acting benzodiazepines

The half-lives of lorazepam, oxazepam (Serax), temazepam (Restoril), and estazolam are between 8 and 30 hours. Alprazolam has a half-life of 10 to 15 hours and triazolam has the shortest half-life (2 to 3 hours) of all the orally administered benzodiazepines.

BENZODIAZEPINES

Insomnia - Temazepam, flurazepam, triazolam, Zolpidem, zaleplon, and eszopiclone

GAD – all benzodiazepines Panic disorder – alprazolam and clonazepam Social phobia – clonazepam and diazepam Other disorders as adjunct – OCD, PTSD MADD – Alprazolam Bipolar –I - Clonazepam, lorazepam, and alprazolam Parkinsons – Zolpidem 10 mg 4 times a day

Chlordiazepoxide (Librium) is used to manage the symptoms of alcohol withdrawal

IM lorazepam is used to manage agitation, both substance-induced (except amphetamine) and psychotic, in the emergency room

Used in catatonia and delusions with associated panic or anxiety

The most common adverse effect of benzodiazepines is drowsiness, which occurs in about 10 percent of all persons

It is a norepinephrine and dopamine reuptake inhibitor. This results in a side-effect profile characterized by little risk of sexual dysfunction or sedation, and with modest weight loss during acute and long-term treatment

Bupropion is a monocyclic aminoketone Comparable to SSRIs in treating depression, even

though SSRI are first line Bupropion - prevents seasonal major depressive

episodes in patients with a history of SAD

BUPROPION

Bupropion is indicated for use in combination with behavioral modification programs for smoking cessation

2nd line agent for ADHD and ADHD with comorbid depression, substance abuse and conduct disorder

As treatment for nondepressed individuals with hypoactive sexual desire disorder. Bupropion may improve sexual arousal, orgasm completion, and sexual satisfaction

Cocaine detox because of dopaminergic effects

Azaperone introduced in 1986 as the first nonsedating drug specifically indicated for the treatment of GAD

Buspirone is a narrow-spectrum antianxiety agent, with demonstrated efficacy only in the treatment of generalized anxiety disorder.

In contrast to the SSRIs or venlafaxine (Effexor), buspirone is not effective in the treatment of panic disorder, OCD, or social phobia

The coadministration of buspirone and benzodiazepines may be effective in the treatment of anxiety disorders that have not responded to treatment with either drug alone

BUSPIRONE

Antimanic agents for persons who are refractory to, or cannot tolerate, treatment with first-line mood-stabilizing agents.

Calcium channel inhibitors include nifedipine (Procardia, Adalat), nimodipine (Nimotop), isradipine (DynaCirc), amlodipine (Norvasc, Lotrel), nicardipine (Cardene), nisoldipine (Sular), nitrendipine, and verapamil (Calan).

CCB

They are used to control mania and ultradian bipolar disorder (mood cycling in less than 24 hours).

Nimodipine – ultradian BPAD and recurrent brief depression

Verapamil – Antidepressant induced mania Calcium channel blockers can be combined with

other agents, such as carbamazepine, in patients who are partial responders to monotherapy

Iminostilbene TCA Acute mania – but takes several days and full effect

only seen in 2-3 weeks, effective in persons who are not responsive to lithium, such as persons with dysphoric mania, rapid cycling, or a negative family history of mood disorders

Preventing relapses, particularly among patients with bipolar II illness, schizoaffective disorder, and dysphoric mania

Refractory depression

CARBAMAZEPINE

Control symptoms associated with acute alcohol withdrawal

paroxysmal recurrent component of posttraumatic stress disorder

effective in controlling impulsive, aggressive behavior in persons of all ages who are not psychotic, including children and the elderly

controlling nonacute agitation and aggressive behavior in patients with schizophrenia and schizoaffective disorder with positive symptoms and hallucinations

Iminostilbene anticonvulsant antipsychotic Effective in approximately half of patients

with bipolar disorder and is well tolerated Associated with a greater enhancement in mood

and reduction in anxiety symptoms than other drugs employed to treat epilepsy

OXCARBAZEPINE

CHOLINESTERASE INHIBITORS AND MEMANTINE

Cholinesterase inhibitors are effective for the treatment of mild to moderate cognitive impairment in dementia of the Alzheimer's type

In long-term use, they slow the progression of memory loss and diminish apathy, depression, hallucinations, anxiety, euphoria, and purposeless motor behaviors

Donepezil and rivastigmine may be beneficial for patients with Parkinson's disease and Lewy body disease

Memantine is the only approved therapy in the United States for moderate to severe Alzheimer's disease

Direct-acting skeletal muscle relaxant, which is used to treat neuroleptic malignant syndrome

Intravenous (IV) dantrolene reduces muscle spasm in about 80 percent of persons with neuroleptic malignant syndrome

Muscle relaxation and a general and dramatic improvement in symptoms can appear within minutes of administration, although in most cases, the beneficial effects can take several hours to appear

Catatonia and serotonin syndrome

DANTROLENE

Alcohol sensitising deterrent agent It deters use of alcohol by producing a rapid and

violently unpleasant reaction in a person who ingests even a small amount of alcohol

The primary indication for disulfiram use is as an aversive conditioning treatment for alcohol dependence

Either the fear of having a disulfiram alcohol reaction or the memory of having had one is meant to condition the person not to use alcohol

DISULFIRAM

Chemical structure similar to that of the amino acid taurine and GABA

Probably antagonist at the NMDA receptors Acamprosate is used for treating alcohol-dependent

individuals seeking to continue to remain alcohol-free after they have stopped drinking

ACAMPROSATE

DOPAMINE RECEPTOR AGONISTS

Used to treat medication-induced parkinsonism, extrapyramidal symptoms, akinesia, and focal perioral tremors

Most clinicians rely on anticholinergics, amantadine (Symmetrel), and antihistamines because they are equally effective and have few adverse effects

Bromocriptine – used in NMS and refractory depression Ropinirole and pergolide - augmentation to antidepressant

therapy and to treat medication-resistant bipolar II depression

Ropinirole may also be helpful in the treatment of antidepressant-induced sexual dysfunction

DOPAMINE RECEPTOR ANTAGONISTS

Rapid neuroleptization (also called psychotolysis) is the practice of administering hourly IM doses of antipsychotic medications until marked sedation of the person is achieved

Long-acting depot preparations may be needed to overcome problems with compliance.

IM preparations are typically given once every 1 to 4 weeks

Lowers seizure threshold Sedation Central anticholinergic effects Thioridazine and mesoridazine – prolong QT interval Chlorpromazine, thioridazine – orthostatic hypotension Temporary leucopenia or agranulocytosis Low potency DRAs can also cause peripheral anticholinergic

symptoms Increases prolactin Anorgasmia and decreased libido Allergic dermatitis and photosensitivity

ADVERSE EFFECTS OF ANTIPSYCHOTICS

Lamotrigine is a novel three-ringed (phenyltriazine) compound, anti-glutamatergic and sodium channel blocker

Maintenance treatment of bipolar disorder, especially rapid cycling and Bipolar - I

Reduces the intervals of depressive episodes rather than manic episodes

LAMOTRIGINE

Lithium (Eskalith, Lithobid, Lithonate) was approved by the US Food and Drug Administration (FDA) for the treatment of mania in 1970, more than 20 years after the first favorable reports by John F. J. Cade, an Australian psychiatrist

Lithium (Li), a monovalent ion, is a member of the group IA alkaline metals on the periodic table

LITHIUM

MELATONIN AGONISTS

Ramelteon essentially mimics melatonin's sleep-promoting properties. It has high affinity for melatonin MT1 and MT2 receptors in the brain

Ramelteon mainly shortens latency to sleep onset and, to a lesser extent, increases total duration of sleep.

Melatonin (N-acetyl-5 methoxytryptamine) is a hormone mainly produced at night in the pineal gland. Its secretion is stimulated by the dark and inhibited by light

It is hypothesized that the antidepressant-like activity of Agomelatine most probably involves a combination of both its melatonin agonist and 5-HT2C receptor antagonist properties

Mirtazapine (Remeron) is unique among drugs used to treat major depression in that it increases both norepinephrine and serotonin through a mechanism other than reuptake blockade

Mirtazapine is effective for the treatment of depression. It is highly sedating, making it a reasonable choice for

use in depressed patients with severe or long-standing insomnia

Mirtazapine is often combined with SSRIs or venlafaxine (Effexor) to augment antidepressant response or counteract serotonergic side effects of those drugs

MIRTAZAPINE

The currently available MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), tranylcypromine (Parnate), and selegiline (Eldepryl). Oral Selegiline is a selective inhibitor of MAOB used for the treatment of parkinsonism

Phenelzine is more effective than tricyclic antidepressants (TCAs) in depressed patients with mood reactivity

The most worrisome side effect of MAOIs is the tyramine-induced hypertensive crisis

MAOI

Structurally related to trazodone, not routinely used Used for treating major depression, panic disorder

and panic with comorbid depression or depressive symptoms, of generalized anxiety disorder, and of premenstrual dysphoric disorder, and for the management of chronic pain

increases sleep continuity Also of use in patients with PTSD and chronic

fatigue syndrome

NEFAZODONE

Methadone is used for short-term detoxification (7 to 30 days), long-term detoxification (up to 180 days), and maintenance (treatment beyond 180 days) of opioid-dependent individuals

Levomethadyl is no longer marketed Buprenorphine - used for opioid maintenance

treatment as sublingual tablets

OPIOID RECEPTOR AGONISTS

The three opioid receptor antagonists are naltrexone (ReVia), Naloxone (Narcan), and nalmefene (Revex)

Naltrexone and nalmefene are competitive antagonists of opioid receptors

Used for opioid dependence Opioid receptor antagonists are also used as

adjuncts to cognitive behavioral programs for treatment of alcohol dependence

OPIOID RECEPTOR ANTAGONISTS

The introduction of the first phosphodiesterase (PDE)-5 inhibitor, sildenafil (Viagra), in 1998 revolutionized the treatment of the major sexual dysfunction affecting men - erectile disorder. Two congeners have since come on the market - vardenafil (Levitra) and tadalafil (Cialis)

These drugs are effective regardless of the baseline severity of erectile dysfunction

Sildenafil has been reported to reverse SSRI-induced anorgasmia in men

Anecdotal reports indicate that sildenafil has a therapeutic effect on sexual inhibition in women as well

PDE-5 inhibitors

Venlafaxine (Effexor), desvenlafaxine, duloxetine(Cymbalta), milnacipran and sibutramine are SNRIs.

Venlafaxine has higher remission rates in depression than SSRIs by 6% The extended-release formulation of venlafaxine is approved for

treatment of GAD, SAD and panic disorder Venlafaxine may be beneficial in the treatment of OCD, agoraphobia,

ADHD, and in patients with a dual diagnosis of depression and cocaine dependence

Duloxetine is formulated as a delayed-release capsule to reduce the risk of severe nausea associated with the drug and used for depression, GAD, diabetic neuropathy and stress urinary incontinence

DVS - depression and for the alleviation of vasomotor symptoms (VMS) associated with menopause

SNRIs

SSRIs

Off-label uses of SSRIs are follows - The antiorgasmic effects of SSRIs make them useful as a

treatment for men with premature ejaculation. SSRIs permit intercourse for significantly longer – fluoxetine and sertraline

SSRIs diminish the average time per day spent in unconventional sexual fantasies, urges, and activities

Sertraline and fluvoxamine have been shown in controlled and open-label trials to mitigate aggressiveness, self-injurious behavior, repetitive behaviors, some degree of language delay, and, rarely, lack of social relatedness in adults with autistic spectrum disorders.

Fluoxetine has been reported to be effective for features of autism in children, adolescents, and adults.

Concurrent administration of an SSRI with an MAOI, L-tryptophan, or lithium can raise plasma serotonin concentrations to toxic levels, producing a constellation of symptoms called the serotonin syndrome

This serious and possibly fatal syndrome of serotonin overstimulation is composed, in order of appearance as the condition worsens, of (1) diarrhea; (2) restlessness; (3) extreme agitation, hyperreflexia, and autonomic instability with possible rapid fluctuations in vital signs; (4) myoclonus, seizures, hyperthermia, uncontrollable shivering, and rigidity; and (5) delirium, coma, status epilepticus, cardiovascular collapse, and death.

Also known as second-generation or atypical antipsychotic drugs

These drugs include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), clozapine (Clozaril), and ziprasidone (Geodon)

They are called SDAs because they have a higher ratio of serotonin type 2 (5-HT2) to D2 dopamine receptor blockades than the typical, or conventional, dopamine receptor antagonists (DRAs) that previously were the mainstay of treatment

SDAs

All of the SDAs share the following characteristics: (1) low D2 receptor blocking effects when compared with DRAs, which have high D2 receptor blockades; (2) a reduced risk of extrapyramidal side effects compared with older agents, a reduced risk that probably extends to the occurrence of tardive dyskinesia as well; (3) proved efficacy as treatments for schizophrenia; and (4) proved efficacy as treatments for acute mania

The SDAs are effective for treating acute and chronic psychoses, such as schizophrenia and schizoaffective disorder, in both adults and adolescents

SDAs are as good as, or better than, typical antipsychotics (DRAs) for the treatment of positive symptoms in schizophrenia and clearly superior to DRAs for the treatment of negative symptoms

Olanzapine is also approved for maintenance treatment of bipolar disorder

A combination of SDAs and antidepressants is frequently used in treatment-resistant depression, and a fixed combination of olanzapine and fluoxetine (Symbyax) is approved by the FDA as a treatment for acute bipolar depression

Other indications include acquired immunodeficiency syndrome (AIDS), autistic spectrum disorders, Tourette's disorder, Huntington's disease, and Lesch-Nyhan syndrome.

Risperidone and olanzapine have been used to control aggression and self-injury in children

Clozapine – Dibenzodiazepine, the most effective drug treatment for patients who have failed on standard therapies

Other clinical situations where clozapine can be used include tardive dyskinesia, the treatment of psychotic patients who are intolerant of extrapyramidal side effects caused by other agents, treatment-resistant mania, severe psychotic depression, idiopathic Parkinson's disease, Huntington's disease, and suicidal patients with schizophrenia or schizoaffective disorder

Other treatment-resistant disorders that have demonstrated response to clozapine include pervasive developmental disorder, autism of childhood, or OCD (either alone or in combination with an SSRI)

Bifeprunox, a dopamine partial agonist, is an investigational atypical antipsychotic for the treatment of schizophrenia

Paliperidone is the major active metabolite of the antipsychotic medication risperidone

Unlike the SDAs, aripiprazole, however, is not a D2 antagonist, but is a partial D2 agonist

Aripiprazole - add-on to SSRIs in treatment-resistant patients with mood or anxiety disorders

Arip also shows 60% response in ODD and conduct disorder patients

Stimulant drugs, also referred to as psychostimulants, mimic the effects of naturally occurring sympathomimetic amines

They increase motivation, mood, energy, and wakefulness Psychostimulants used in psychiatry include methylphenidate

(Ritalin), dexmethylphenidate (Focalin), dextroamphetamine (Dexedrine), a combination of amphetamine and dextroamphetamine (Adderall), and pemoline (Cylert), now considered a second-line agent because of rare but potentially fatal hepatic toxicity

Modafinil (Provigil), has been used as an antidepressant and a treatment for ADHD

Atomoxetine (Strattera), although not a stimulant, is indicated for use in ADHD and is included in this section

Sympathomimetics used for appetite suppression include methamphetamine (Desoxyn), phentermine (Adipex-P, Ionamin), diethylpropion (Tenuate), and phendimetrazine (Bontril)

SYMPATHOMIMETIC STIMULANTS

ADHD - Methylphenidate is the most commonly used initial agent

Modafinil is approved as an antisomnolence agent for treatment of narcolepsy, for people who cannot adjust to night shift work, and for those who do not sleep well because of obstructive sleep apnea

Dextroamphetamine may be useful in differentiating pseudodementia of depression from dementia

Sympathomimetics increase alertness, cognition, motivation, and motor performance in persons with neurologic deficits caused by strokes, trauma, tumors, or chronic infections

Depression in medically ill persons, especially persons with acquired immunodeficiency syndrome (AIDS); obtundation because of chronic use of opioids; and clinical situations in which a rapid response is important but for which electroconvulsive therapy (ECT) is contraindicated

Sympathomimetics are used in the treatment of obesity because of their anorexia-inducing effects

Fatigue - Modafinil, amphetamines, methylphenidate, are sometimes effective in combating this symptom in MS patients and CFS

Thyroid hormones levothyroxine (Synthroid, Levothroid, Levoxine) and liothyronine (Cytomel) are used in psychiatry, either alone or as augmentation to treat persons with depression or rapid-cycling bipolar I disorder

Convert an antidepressant-nonresponsive person into an antidepressant-responsive person

Liothyronine has been used primarily as an adjuvant for tricyclic drugs; however, evidence suggests that liothyronine augments the effects of all the antidepressant drugs

THYROID HORMONES

Trazodone is structurally related to nefazodone (Serzone)

The main indication for the use of trazodone is major depressive disorder

Trazodone is a first-line agent for the treatment of insomnia because of its marked sedative qualities and favorable effects on sleep architecture

Trazodone is associated with an increased risk of priapism

TRAZODONE

TRICYCLICS AND TETRACYCLICS

The treatment of a major depressive episode and the prophylactic treatment of major depressive disorder are the principal indications for using TCAs

Imipramine is the TCA most studied for panic disorder with agoraphobia

Doxepin – GAD OCD appears to respond specifically to clomipramine, as

well as the SSRIs Amitriptyline is the TCA most often used in pain syndromes Clomipramine - Premature ejaculation, movement

disorders, and compulsive behavior in children with autistic disorders

Valproate is a simple-chain branch carboxylic acid. It is called valproic acid because it is rapidly converted to the acid form in the stomach

Multiple formulations of valproic acid are marketed These include valproic acid (Depakene); divalproex

sodium (Depakote), an enteric-coated delayed release 1:1 mixture of valproic acid and sodium valproate; and sodium valproate injection (Depacon). An extended-release preparation is also available

VALPROATE

About two thirds of persons with acute mania respond to valproate

Divalproex sodium ER tablets are approved for the treatment of acute manic or mixed episodes, with or without psychotic features

Short-term treatment of depressive episodes in bipolar I disorder

prophylactic treatment of bipolar I disorder, rapid-cycling and ultrarapid-cycling bipolar disorders, dysphoric mania

Valproate may accelerate response to antipsychotic therapy in patients with schizophrenia or schizoaffective disorder

YOHIMBINE

Yohimbine hydrochloride is derived from an alkaloid found in Rubaceae and related trees and in the Rauwolfia serpentina plant

Yohimbine has been used to treat erectile dysfunction, but now replaced by PDE-5 inhibitors

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