Antipsychotic Agents

Introduction
• The term “psychosis” denotes a variety of mental disorders that are
characterized by the inability to distinguish between what is real and
what is not:
– the presence of delusions (false beliefs)
– various types of hallucinations
• usually auditory or visual, but sometimes tactile or olfactory

– grossly disorganized thinking

• Schizophrenia is a particular kind of psychosis characterized mainly by

a marked thinking and perceptual disturbance.
• Schizophrenia is the most common psychotic disorder.
• Schizophrenia is considered to be a neurodevelopmental
disorder
– implying that structural and functional changes in the brain are
present even in utero in some patients, or that they develop during
childhood and adolescence, or both.
– schizophrenia is a genetic disorder with high heritability.
– No single gene is involved.
– involves multiple genes with common and rare mutations, including
large deletions and insertions (copy number variations)
The serotonin hypothesis

• 5-HT2A and 5-HT2C receptor stimulation is the basis for the

hallucinatory effects of LSD and mescaline, both serotonin

agonists.

• 5-HT2A receptor blockade is a key factor in the mechanism of

action of the main class of atypical antipsychotic drugs.

The serotonin…

• Atypical antipsychotic drugs are inverse agonists of the 5-

HT2A receptors: they block the constitutive activity of these

receptors.

• 5-HT2A receptors modulate the release of dopamine,

norepinephrine, glutamate, GABA and acetylcholine in the

cortex, limbic region and striatum.

The serotonin…

• Stimulation of 5-HT2A receptors leads to depolarization of

glutamate neurons, but also stabilization of N-methyl-D-

aspartate (NMDA) receptors on postsynaptic neurons.

• Hallucinogens can modulate the stability of a complex

consisting of 5-HT2A and NMDA receptors.

The serotonin…

• 5-HT2C receptor stimulation provides a further means of

modulating cortical and limbic dopaminergic activity.

• Stimulation of 5-HT2C receptors leads to inhibition of cortical

and limbic dopamine release.

• Clozapine, asenapine and olanzapine are 5-HT2C inverse

agonists.
The dopamine hypothesis

• Excessive limbic dopaminergic activity plays a role in psychosis.

• Many antipsychotic drugs strongly block postsynaptic D2

receptors in the CNS, especially in the mesolimbic and striatal-

frontal system.

• This includes partial dopamine agonists, such as aripiprazole and

bifeprunox.
The dopamine…

• Drugs that increase dopaminergic activity (levodopa,

amphetamines, bromocriptine, apomorphine) either aggravate

schizophrenia psychosis or produce psychosis de novo in some

patients.
The dopamine…

• Dopamine-receptor density has been found postmortem

to be increased in the brains of schizophrenics who have

not been treated with antipsychotic drugs.

• Some postmortem studies of schizophrenic subjects have

reported increased dopamine levels and D2- receptor

density in the nucleus accumbens, caudate and putamen.

The dopamine…

• Diminished cortical or hippocampal dopaminergic activity has been

suggested to underlie the cognitive impairment and negative

symptoms of schizophrenia.

• Decreased dopaminergic innervation in medial temporal cortex,

dorsolateral prefrontal cortex and hippocampus

• Decreased levels of dopamine metabolite DOPAC (Dihydroxy

phenylacetic acid)
The glutamate hypothesis

• Glutamate is the major excitatory neurotransmitter in the

brain.

• Phencyclidine and ketamine are noncompetitive inhibitors of

the NMDA receptor that exacerbate both cognitive

impairment and psychosis in patients with schizophrenia.

The glutamate…

• Hypofunction of NMDA receptors, located on GABAergic

interneurons, leads to diminished inhibitory influences on

neuronal function and contributes to schizophrenia.

• The diminished GABAergic activity can induce disinhibition of

downstream glutamatergic activity.

• This can lead to hyperstimulation of cortical neurons through non-

NMDA receptors.
Manifestations

• Positive/active symptoms any change in behaviour or

thoughts which include thought disturbances, delusions,

hallucinations

• Negative/passive symptoms include social withdrawal, loss of

drive, diminished affect, paucity of speech, impaired personal

hygiene
Older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones
Newer antipsychotic drugs (Atypical)
 Comparisons b/n typical
• Phenothiazines
– Low potency
– Are sedative
– Block D2 receptors
– Metabolism and removal is
slow
– cause extra pyramidal
symptoms
• Butyrophenones
– High potency
– Non-sedative
– Block D2 receptors
– Metabolism and removal is
quicker
– Cause extra pyramidal
symptoms
What Defines “Atypical” Antipsychotics?
• Atypical APD‟s have some of the following:
– Positive Sx: Increased Therapeutic Efficacy
• i.e. in treatment resistant patients
– Negative Sx: Some Therapeutic Efficacy
• motivation, social withdrawl, cognition
– Side Effects: Generally less than typical drugs
• Acute EPS: Parkinsonian, Dyskinesias, Akathisia
• Chronic EPS: Tardive Dyskinesia
• Endocrine: Hyperprolactinemia
New Generations atypical

• Clozapine

• Risperidone

• Olanzapine

• Sertindole

• Quetiapine

• Aripiprazole

• Ziprasidone etc
• MARTA (multi acting receptor targeted agents)
– clozapine, olanzapine, quetiapine

• SDA (serotonin-dopamine antagonists)

– risperidone, ziprasidone, sertindole

• Selective D2/D3 antagonists

– sulpiride, amisulpiride

• Partial Dopamine antagonists

– aripiprazole
Clozapine
• Selectively blocks dopamine D2 receptors relieves positive
symptoms, avoiding nigrostriatal pathway (minimal EPS).
• More strongly blocks 5-HT2 receptors in cortex
relieves negative symptoms.
• Clozapine's antagonism of adrenergic a1 receptors may explain the
orthostatic hypotension.
• Clozapine's antagonism of histamine H1 receptors may explain the
somnolence.
• Side Effects: Increased risk for seizures (2-3%), Agranulocytosis in 1%
Risperidone
• Fewer side effects than Clozapine
• Blocks selective D2, norepinephrine, and 5-HT2
• Argued as effective for positive and negative symptoms
• Extrapyramidal side effects low (but are shown at high doses)
• Shares sedation, weight gain, rapid heart beat, orthostatic
hypotension, and elevated prolactin
• No risk of agranulocytosis
Olanzapine

• Improves negative symptom reduction

• Have lower risk of inducing extrapyramidal side effect

• Does not cause prolactin elevation

• Reduced risk of agranulocytosis

Quetiapine
• No increased risk for extrapyramidal symptoms
• Shares sedation, orthostatic hypotension, weight gain
• Does cause anticholinergic side effects (like older AP and
Clozapine) – dry mouth, constipation
• Does not elevate prolactin

Ziprasidone
• Similar to advantages of others, but argued not to cause
weight gain
Relative receptor-binding affinities of Antipsychotics
Adverse Effects
• Sedation

• Postural hypotension adrenergic blockade

• Anticholinergic effects - include blurred vision, dry mouth, constipation, urinary

retention; results from muscarinic cholinergic blockade

• Endocrine effects - increased prolactin secretion can cause galactorhea; results

from antidopamine effect

• Hypersensitivity reactions - jaundice, photosensitivity, rashes, agranulocytosis

can occur

• Idiosyncratic reactions - malignant neuroleptic syndrome

• Weight gain : especially with clozapine and olanzapine

Neuroleptic Malignant Syndrome
• Occurs in pt’s who are extremely sensitive to the EPS of
antipsychotic agents.
• Due to excessively rapid blockade of postsynaptic dopamine
receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue.
• The stress leukocytosis and high fever associated with this
syndrome may be mistaken for an infection.
Extrapyramidal side-effects
• Acute dystonia: involuntary muscular contraction which results
in abnormal posture or movement.

• Parkinsonism: tremor, rigidity, bradykinesia.

• Akathisia: sensation of inner restlessness, a compulsion to

keep moving. Patients may be observed repeating purposeless
movements.

• Tardive dyskinesia: rhythmic involuntary movements of tongue

face and jaw.
Mood Disorder
Schizoaffective disorder
• Schizoaffective disorder includes features of both
schizophrenia and a mood disorder such as bipolar disorder or
depression.

– "schizo-" refers to the psychotic symptoms of schizophrenia

that affect a person's thinking, sense of self, and
perceptions.

– "-affective" refers to extreme shifts in mood, energy, and

behavior.
Bipolar disorder
• Bipolar disorder, once known as manic-depressive illness. The
key symptoms of bipolar disorder
Manic phase Depressive phase
• expansive or irritable mood • depressed mood
• hyperactivity, impulsivity • diurnal variation
• diminished need for sleep • sleep disturbance
• racing thoughts • anxiety
• psychotic symptoms in some • sometimes, psychotic symptoms.
• cognitive impairment
Types of bipolar disorder
• Bipolar disorder type I: is the classic form of the disease in
which patients have periodic episodes of mania and
depression.

• Bipolar disorder type II: patients do not develop severe mania

but go through episodes of hypomania that alternate with
milder depression.

• Rapid cycling bipolar disorder: when patients exhibit more

than four manic or depressive episodes occur during a one
year period.
Types of mood stabilizers

1. Lithium

2. Anticonvulsant medicines

3. Antipsychotic medicines
Lithium
• Lithium is a small monovalent cation.

• The biochemical basis for mood stabilizer therapies including lithium

and anticonvulsant mood stabilizers is not clearly understood.

• The suggested mechanism

A. Effects on Electrolytes and Ion Transport

– Due to Lithium resemblance to sodium, it can substitute for sodium in
generating action potentials and in Na+-Na+ exchange across the membrane.
B. Effects on Second Messengers
1. Interference with inositol triphosphate formation:
– The phosphatidylinositol(pi)pathway is blocked at a point where inositol
phosphate is hydrolyzed to free inositol.
– This step is required for the regeneration of PI in the membrane after it
has been hydrolyzed by agonist action.
2. Interference with cAMP production:
– hormone induced cAMP production is reduced
– E.g.: The response of renal tubular cells to ADH and of thyroid to TSH
– Effect of lithium on these2 second messenger systems accounts for its therapeutic
effects.
Lithium toxicity

• Lithium therapy requires reaching plasma concentrations of

lithium which are relatively close to the toxic concentration.

• Depletion of sodium reduces the rate of excretion of lithium by

increasing reabsorption of lithium from proximal tubule .

• Diuretics acting on proximal tubule have the same effect.

• Renal diseases also predispose to lithium toxicity.

Side effects of lithium
• N/V/D
• Tremor
• Increased thirst
• Weight gain in the first few months of use
• Drowsiness
• A metallic taste in the mouth
• Abnormalities in kidney function
• Abnormalities in thyroid function
Contraindications of lithium

• Renal or cardiovascular disease

• Sodium depletion

• Dehydration

• Patients on diuretics

• During pregnancy and lactation

Anticonvulsants
Valproate
• Is a simple monocarboxylic acid.
• now the 1st choice for treatment of mania (even over Li)
• less effective than Li in treating mania, but does also help
decrease depression more effectively than Li
• Is especially good for treatment of acute mania (alone or with
antipsychotic meds)
• Has low toxicity and lacks sedation.
MoA of Valproate

• a GABA agonist (enhances synthesis/release of GABA)

• Is a weak inhibitor of GABA transaminase and succinic semi

aldehyde dehydrogenase.

• a glutamate antagonist

• 50% plasma protein bound

• is a liver enzyme inhibitor (of P450 enzymes)

Lamotrigine

• delays the time between mood changes and manic or

depressive states by decreasing the intensity of irregular

electrical activity in the brain.

• more effective as a mood stabilizer in preventing relapses in

treating bipolar II disorder.

Carbamazepine
• It tends to cause more side effects than valproate and is less
effective than lithium.

• It is usually only used in people who have been unresponsive

to lithium.

• It may be better for rapid cycling bipolar illness.

• Carbamazepine causes unwanted side effects, and it can also

interact with several other medicines.
P’kinetics

• Is well absorbed.

• 75% protein bound.

• Plasma half life is about 30 hours when given as a single dose

and shortens to 15 hours when given repeatedly.

• Is a liver enzyme inducer (CYP-3A4 especially)

Antipsychotics
• Antipsychotics can be
• Typical antipsychotics
– Phenothiazines: fluphenazine, Chlorpromazine
– Thioxanthines: chlorprothixene, thiothixene
– Butyrophenones: haloperidol, droperidol

• Atypical antipsychotics
– Clozapine, risperidone, olanzapine quetiapine sertindole,
aripiprazole
Antidepressant Agents
Introduction

• Major depressive disorder (MDD) is characterized by

– Depressed mood most of the time for at least 2 weeks or

– Loss of interest or pleasure in most activities

– Disturbances in sleep

– Appetite as well as deficits in cognition and energy

– Thoughts of guilt/worthlessness

– Thoughts of suicide etc…

Intro…
• Antidepressants have broad application in addition to MDD for

– Panic disorder

– Generalized anxiety disorder (GAD)

– Post-traumatic stress disorder (PTSD)

– Obsessive-compulsive disorder (OCD)

– Neuropathic pain and the pain associated with fibromyalgia.

PATHOPHYSIOLOGY MDD

• A deficit in function or amount of

– Monoamine hypothesis

– Neurotrophic factors

– Endocrine factors
Neurotrophic Hypothesis
• Nerve growth factors such as brain-derived neurotrophic factor
(BDNF) are critical in the regulation of neural plasticity, resilience, and
neurogenesis.
• Suggests that depression is associated with the loss of neurotrophic
support
– effective antidepressant therapies increase neurogenesis and synaptic
connectivity in cortical areas as well as the hippocampus.

• BDNF is thought to exert its influence on neuronal survival and

growth effects by activating the tyrosine kinase receptor B in both
neurons and glia
Monoamines & Other Neurotransmitters

• The monoamine hypothesis of depression suggests that depression is

related to a deficiency in the amount or function of cortical and limbic

serotonin (5-HT)

norepinephrine (NE)

and dopamine (DA)

Monoamines…
• Reserpine treatment, which is known to deplete monoamines, is
associated with depression in a subset of patients.
• Serotonergic antidepressants such as fluoxetine often rapidly suffer
relapse when Pt’s given diets free of tryptophan, a precursor of serotonin
synthesis.
• Administration of an inhibitor of norepinephrine synthesis is also
associated with a rapid return of depressive symptoms
• All available antidepressants appear to have significant effects on the
monoamine system.
– All classes of antidepressants appear to enhance the synaptic availability of 5-HT,
norepinephrine, or dopamine.
Monoamines…

• Depressed patients found to have elevated glutamate content in the

CSF of depressed patients.

• A number of preclinical and clinical studies have demonstrated rapid

antidepressant effects of ketamine.

– Ketamine is a potent, high-affinity, noncompetitive NMDA receptor

antagonist
Neuroendocrine Factors
• More severe types of depression, tend to be associated with HPA
abnormalities more commonly than milder forms of major depression.

• Both exogenous glucocorticoids and endogenous elevation of cortisol are

associated with mood symptoms and cognitive deficits similar to those
seen in MDD.

• Thyroid dysregulation has also been reported in depressed patients.

• Sex steroids are also implicated in the pathophysiology of depression.

• Estrogen deficiency states, which occur in postmenopausal periods, are

thought to play a role in the etiology of depression in some women.
BASIC PHARMACOLOGY OF ANTIDEPRESSANTS

A. Selective Serotonin Reuptake Inhibitors (SSRI)

B. Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

C. 5-HT2 Receptor Modulators

D. Tetracyclic and Unicyclic Antidepressants

E. Monoamine Oxidase Inhibitors

Selective Serotonin Reuptake Inhibitors
SSRIs…
• All of the SSRIs are orally active
• Once-daily dosing.
• Hepatic metabolism: CYP2D6
• Fluoxetine and paroxetine are potent inhibitors of the CYP2D6
isoenzyme, and this contributes to potential drug interactions.
• Fluvoxamine is an inhibitor of CYP3A4.
• Care should be used in combining SSRIs with drugs that are
metabolized by CYPs 1A2, 2D6, 2C9, and 3A4 (e.g., Warfarin, tricyclic
antidepressants, paclitaxel)
SSRIs MoA
• SSRI initially blocks SERT and results in enhanced serotonergic
neurotransmission by blocking the reuptake of serotonin by SERT.
• Increased synaptic availability of serotonin stimulates a large number of
postsynaptic 5-HT receptor subtypes, as well as presynaptic terminal
receptors that regulate serotoninergic neuron activity and serotonin
release.
• SSRI treatment causes stimulation of 5-HT 1A and 5-HT7 autoreceptors on
cell bodies in the raphe nucleus and of 5-HT 1D autoreceptors on
serotonergic terminals, and this reduces serotonin synthesis and release
toward pre-drug levels.
SSRIs MoA…
• With repeated treatment with SSRIs, there is a gradual down
regulation and desensitization of these autoreceptors.

• In addition, down-regulation of postsynaptic 5-HT2A receptors may

contribute to antidepressant efficacy directly or by influencing the
function of noradrenergic and other neurons via serotonergic
heteroreceptors.

• Other postsynaptic 5-HT receptors likely remain responsive to

increased synaptic concentrations of 5-HT and contribute to the
therapeutic effects of the SSRIs.
SSRIs uses

• Depression

• Anxiety : generalized anxiety, panic, social anxiety

• Posttraumatic stress disorder (Sertraline and Paroxetine )

• Premenstrual dysphoric syndrome

• Vasovagal symptoms in post-menopausal

• Obsessive-compulsive disorder
SSRIs ADVERSE EFFECTS
• Excessive stimulation of brain 5-HT2 receptors : insomnia, increased

anxiety, irritability, and decreased libido.

• Excess activity at spinal 5-HT2 receptors : sexual side effects including

erectile dysfunction, anorgasmia, and ejaculatory delay

• Stimulation of 5-HT3 receptors in the CNS and periphery - GI effects :

nausea , diarrhea and emesis.

• Withdrawal syndrome : dizziness, headache, nervousness, nausea, and

insomnia.
SSRIs DRUG INTERACTIONS
• Since MAOIs bind irreversibly to MAO and block the enzymatic
metabolism of monoaminergic neurotransmitters, SSRIs should not
be started until at least 14 days following discontinuation of
treatment with MAOI; this allows for synthesis of new MAO.
• For all SSRIs except Fluoxetine, at least 14 days should pass prior to
beginning treatment with MAOI following the end of treatment with
an ssri.
• Since the active metabolite norfluoxetine has a t1/2 of 1-2 weeks,
at least 5 weeks should pass between stopping fluoxetine and
beginning MAOI.
SSRIs DRUG INTERACTIONS…
• MAOIs enhance the effects of SSRIs due to inhibition of
serotonin metabolism.

• Serotonin syndrome : Hyperthermia, muscle rigidity,

myoclonus, tremors, autonomic instability, confusion,
irritability, and agitation; this can progress toward coma and
death.
Serotonin-Norepinephrine Reuptake Inhibitors
1. Selective serotonin-norepinephrine reuptake inhibitors
• The elimination half-life : Venlafaxine - 5 hours Desmethylvenlafaxine -

11 hours

• Desmethylvenlafaxine is eliminated by hepatic metabolism and by

renal excretion.

• Duloxetine has a t1/2 of 12 hours.

VENLAFAXINE

• The reuptake effects of venlafaxine are dose-dependent.

• At low doses (<150 mg/day), it acts only on serotonergic transmission.

• At moderate doses (>150 mg/day), it acts on serotonergic and

noradrenergic systems

• Whereas at high doses (>300 mg/day), it also affects dopaminergic

neurotransmission.
SNRIs MECHANISM OF ACTION
• SNRIs inhibit both SERT and NET.

• SNRIs cause enhanced serotonergic and/or noradrenergic

neurotransmission.

• The initial inhibition of SERT induces activation of 5-HT1A and 5-HT1D

autoreceptors.

• This action decreases serotonergic neurotransmission by a negative

feedback mechanism until these serotonergic autoreceptors are
desensitized.

• Then, the enhanced serotonin concentration in the synapse can interact

with postsynaptic 5-HT receptors.
USES OF SNRIs
• Major Depressive Disorder
• Generalized Anxiety Disorder
• Social Anxiety Disorder
• Panic Disorder
• Neuropathic Pain (Duloxetine)
• Fibromyalgia (Milnacipram , Duloxetine)
• Chronic Musculoskeletal Pain
• Stress Urinary Incontinence (Duloxetine)
• PTSD (Venlafaxine)
SNRIs ADVERSE EFFECTS

• Nausea, constipation, insomnia, headaches, and sexual

dysfunction.

• Venlafaxine : cardiotoxicity

• Duloxetine : hepatic failure

SNRIs DRUG INTERACTIONS

• While 14 days are suggested to elapse from ending MAOI therapy

and starting Venlafaxine treatment, an interval of only 7 days after

stopping Venlafaxine is considered safe before beginning MAOI.

• Duloxetine has a similar interval to initiation following MAOI

therapy, but requires only a 5-day waiting period to begin MAOI

treatment after ending Duloxetine.

Serotonin-Norepinephrine Reuptake Inhibitors
2. Tricyclic antidepressants
Tricyclic Antidepressants

• The TCAs, or their active metabolites, have plasma exposure half-lives of 8-

80 hours; once-daily dosing.

• Steady-state concentrations occur within several days to several weeks of

beginning treatment.

• TCAs are largely eliminated by hepatic CYPs.

• Determination of plasma levels may be useful in identifying patients who

appear to have toxic effects and may have excessively high levels of the drug.
TCAs MoA

• SERT and NET blocker (Imipramine, Amitriptyline)

• NET blocker (Desipramine, Nortriptyline, Protriptyline,

Amoxapine):- (H1, 5-HT2, Alpha1, and Muscarinic).

• Amoxapine - also a dopaminergic receptor antagonist :

extrapyramidal side effects such as tardive dyskinesia.

TCAs ADVERSE EFFECTS
• H1 receptor antagonism : sedative effects of TCAs
• Antagonism of muscarinic receptors : cognitive dulling , blurred
vision, dry mouth, tachycardia, constipation, difficulty urinating.
• Antagonism of α-1 adrenergic receptors : orthostatic hypotension and
sedation.
• Weight gain.
• Quinidine-like effects on cardiac conduction : limit the use of TCAs in
patients with coronary heart disease.
• TCAs also lower the seizure threshold.
TCAs DRUG INTERACTIONS
• Drugs that inhibit CYP2D6, such as SSRIs, may increase plasma
exposures of TCAs.

• TCAs can potentiate the actions of sympathomimetic amines

and should not be used concurrently with MAOIs or within 14
days of stopping MAOIs.
Tetracyclic and Unicyclic Antidepressants
5-HT2 Receptor Modulators
5-HT2 Receptor Modulators
• Trazodone and nefazodone are rapidly absorbed and undergo hepatic
metabolism.
• Both trazodone and nefazodone have active metabolites that also
exhibit 5-HT2 antagonism.
• Nefazodone is a potent inhibitor of the CYP3A4 system and may
interact with drugs metabolized by this enzyme
• Trazodone : Elimination t1/2 : 7-10 hours
• Nefazodone : Elimination t1/2 : 2-4 hours
• Mirtazapine : Elimination t1/2 : 20 to 40 hours
MoA
• TRAZODONE : Blocks 5-HT2A receptor, inhibits reuptake of 5-HT and

desensitizes 5-HT autoreceptor, enhances 5-HT release.

• TRAZODONE also blocks Alpha1 adrenergic receptors.

• NEFAZODONE : blockade of the 5-HT2 receptors.

• MIRTAZAPINE: Tetracyclic structure : stimulates norepinephrine and serotonin

release through its central presynaptic Alpha2-adrenergic antagonist effects ;

potent antagonist of 5-HT2c and histamine receptors

• MIANSERIN: blocks presynaptic Alpha2 receptors

Uses of 5-HT2 Receptor Modulators

• Depression : Trazodone typically is started at 150 mg/day in

divided doses with 50 mg increments every 3-4 days.

• The maximally recommended dose is 400 mg/day for

outpatients and 600 mg/day for inpatients.

• Insomnia : Low doses of Trazodone (50-100 mg)

• Depressed patients with Insomnia : Mianserin and Mirtazapine

5-HT2 Receptor Modulators ADVERSE EFFECTS

• Trazodone : Blurred vision, Dizziness, Headache ,

Drowsiness, Dry mouth, Fatigue, Nausea, vomiting,

Postural Hypotension , Priapism.

• Mirtazapine : somnolence, increased appetite, weight

gain, Xerostomia, constipation.

5-HT2 Receptor Modulators DRUG INTERACTIONS

• Trazodone dosing may need to be lowered when given

together with drugs that inhibit CYP3A4.

• Trazodone and nefazodone are weak inhibitors of serotonin

uptake and should not be administered with MAOIs due to

concerns about the serotonin syndrome.

BUPROPION

• Bupropion and its major metabolite hydroxybupropion are

modest to moderate inhibitors of norepinephrine and

dopamine reuptake

• May act through dopaminergic or noradrenergic pathways

• Bupropion has virtually no direct effects on the serotonin

system.
BUPROPION PHARMACOKINETICS

• Peak serum time: 2 hr (immediate-release)

3 hr (extended-release)

• Metabolism : Hepatic via CYP2B6

• Elimination t1/2 : 8-24 hours

• Elimination : hepatic and renal

Uses of BUPROPION

• Depression : Bupropion is widely used in combination with

SSRIs

• Prevention of seasonal depressive disorder

• Smoking cessation treatment

• ADHD: 150 mg per day

• Neuropathic pain : 150 mg BD for 6 weeks

BUPROPION ADVERSE EFFECTS
• Headache

• Dizziness

• Insomnia

• Agitation

• Dry mouth

• Nausea

• Risk of seizures
BUPROPION DRUG INTERACTIONS

• The major route of metabolism for Bupropion is CYP2B6

• Consideration for a decreased dose should be made in

cases of -

• Patients with severe hepatic cirrhosis

• Renal impairment
Monoamine Oxidase Inhibitors

• MOCLOBEMIDE
• SELEGILINE
• ISOCARBOXAZID
MAOIs
• MAOIs are metabolized by acetylation.

• A significant portion of the population are "slow acetylators“ and will

exhibit elevated plasma levels.

• The nonselective MAOIs used in the treatment of depression are

irreversible inhibitors ; thus, it takes up to 2 weeks for MAO activity to
recover, even though the parent drug is excreted within 24 hours.

• Recovery of normal enzyme function is dependent on synthesis and

transport of new MAO to monoaminergic nerve terminals.
MoA of MAOIs

• MAOIs are classified by their specificity for MAO-A or -B and whether

their effects are reversible or irreversible.

• Phenelzine and tranylcypromine are examples of irreversible,

nonselective MAOIs.

• Moclobemide is a reversible and selective inhibitor of MAO-A.

• Selegiline is an irreversible MAO-B–specific agent at low doses.

ADVERSE EFFECTS of MAOIs
• HYPERTENSIVE CRISIS :
• MAO-A within the intestinal wall and MAO-A and MAO-B in
the liver normally degrade dietary tyramine.
– However, when MAO-A is inhibited, the ingestion of certain aged
cheeses, red wines, fava beans, and a variety of other tyramine-
containing foods leads to accumulation of tyramine in adrenergic
nerve endings and neurotransmitter vesicles and induces
norepinephrine and epinephrine release.

• HEPATOTOXICITY
DRUG INTERACTIONS of MAOIs
• CNS depressants including Meperidine and other narcotics, alcohol,
and anesthetic agents should not be used with MAOIs.

• Meperidine and other opioid agonists in combination with MAOIs also

induce the serotonin syndrome.

• SSRIs and SNRIs are contraindicated in patients on MAOIs, and vice

versa, to avoid the serotonin syndrome.

• In general, other antidepressants such as TCAs and bupropion also

should be avoided in patients taking an MAOI.
ANXIOLYTICS
ANXIETY
• Unlike other mental disorders, anxiety can be both:
– a normal emotion

– and a psychiatric illness.

• It is a universal human emotion, and a certain amount is useful to

the individual, acting as a stimulant and increasing efficiency.

• but when it becomes excessive and disproportionate in intensity to

the actual danger, an anxiety state develops; it becomes a
pathological (disabling) and needs treatment.
Anxiety Classification

• Anxiety disorder can be classified

– Primary

– Secondary
ANXIETY…
• Panic disorder (PD)
– Sudden overwhelming experience of terror
– Types: Unexpected, Situational

• Phobia
– Specific phobia:
• persistent, excessive, unrealistic fear of a specific object/situation
• fear of specific objects or situations
• For example: public speaking, elevators, animals etc.

– Social phobia
• is an intense fear of social situations

• Obsessive-compulsive disorder (OCD)

– are recurring thoughts or impulses that are intrusive or inappropriate and cause the sufferer
anxiety
ANXIETY…
• Posttraumatic stress disorder (PTSD)
– Exposure to traumas such as a serious accident, a natural disaster, or
criminal assault can result in PTSD.

– When the aftermath of a traumatic experience interferes with normal

functioning, the person may be suffering from PTSD.

• Generalized anxiety disorder (GAD)

– Excessive uncontrollable worry about everyday things.

– This constant worry affects daily functioning and can cause physical
symptoms.
• Pharmacotherapy
– Antidepresssants

– Anxiolytics

– Antipsychotics

– Mood stabilizers

• Psychotherapy- Cognitive Behavior Therapy

BUSPIRONE

• Totally different anxiolytic from BZs,

• no effects on GABA systems, possible partial agonist at 5-HT1A

receptors some affinity for D2 & 5-HT2A.

• Indication:

• Indicated for generalized anxiety disorders but takes 1 to 2

weeks to exert anxiolytic effects.

BUSPIRONE…
• Buspirone lacks anticonvulsant and Muscle relaxant property
of BZs and cause minimal sedation.
• No additive CNS depression with other drugs.
• Adverse effects:
• hypothermia
• increase prolactin
• headache
• dizziness
• nervousness
Benzodiazepines

• Reduction of anxiety at low dose: alprazolam, lorazepam,

oxazepam, diazepam and chlordiazepoxide.

– Alprazolam has anxiolytic-antidepressant effect.

– Diazepam is preferred in acute panic-anxiety.

– Chlordiazepoxide is preferred in chronic anxiety states.

Miscellaneous Agents
• Hydroxyzine competes with histamine for binding at H1-
receptor sites

• Doxylamine acts by competitively inhibiting histamine at

H1 receptors.

• Propranolol-Effective for discrete social phobia i.e.

performance anxiety (inhibits sympathetic overactivity)

• Atypical antipsychotics at low doses for augmentation in

difficult to treat OCD pts