Psychiatry drugs pdf - غير معروف

Antipsychotics

Dr.Nasser A. H. Al-Harchan

Asst. Prof. of Pharmacology

College of Medicine

Baghdad University

Schizophrenia

Etiology

Exact etiology unknown

Genetic predisposition

Intrauterine, birth or postnatal complications

Viral CNS infections

Environmental stressors (biochemical or social)

No evidence of association with poor

parenting

Schizophrenia

Pathophysiology

No consistent neuropathology or

biomarkers for schizophrenia

? Increased dopamine in mesolimbic

pathways causes delusions and hallucinations

? Dopamine deficiency in mesocortical and

nigrostriatal pathways causes negative

symptoms (apathy, withdrawal)

Hallocinogens produce effect through action

on 5-HT2 receptors

Schizophrenia

Antipsychotics

Typical / Conventional antipsychotics

Atypical antipsychotics

Typical / conventional

antipsychotics

Dopamine receptors in various tracks

Track

Origin

Innervations

Function

Antipsychotic

effect

Mesolimbic

Midbrain,

Midbrain,
Ventral

Ventral

tegmental

Limbic

structure,

nucleus

accumbens

Emotional and

intellectual

òHallucinations,

Hallucinations,

deulsions,

disordered

cognition

Mesocortical

Mesocortical Ventral

Ventral

tegmental

Frontal

cortex

Nigrostriatal

Substantia

nigra

Basal ganglia

Basal ganglia Extrapyramidal

Extrapyramidal

system

movement

ñMotor

Motor

symptomatology

Tubero

Tubero--

infundubular

Hypothalamus

Hypothalamus Pituitary

Pituitary

gland

Regulate

endocrine

functions

ñPlasma

Plasma

prolactin levels

Typical / conventional

antipsychotics

Mechanism of action

Blocks receptors for dopamine,

acetylcholine, histamine and

norepinephrine

Current theory suggests dopamine2 (D2)

receptors suppresses psychotic symptoms

All typical antipsychotics block D2 receptors

Close correlation between clinical potency and

potency as D2 receptor antagonists

Typical / conventional

antipsychotics

Properties

Effective in reducing positive symptoms during

acute episodes and in preventing their

reoccurrence

Less effective in treating negative symptoms

Some concern that they may exacerbate negative

symptoms by causing akinesia

Higher incidence of EPS / sedation /

anticholinergic Adverse effects

Typical / conventional

antipsychotics

Potency

All have same ability to relieve symptoms

of psychosis

Differ from one another in terms of

potency

i.e. size of dose to achieve a given response

When administered in therapeutically

equivalent doses, all drugs elicit

equivalent antipsychotic response

Typical / conventional

antipsychotics

Low potency

Chlorpromazine, thioridazine

Medium potency

Perphenazine

High potency

Trifluoperazine, thiothixene, fluphenazine,

haloperidol, pimozide

Typical / conventional

antipsychotics

Potency

Drug

Equiv

oral

dose

(mg)

EPS

Sedation

Anticholinergic s/e

Low

Chlorpromazine 100

Moderate High

Moderate

Pericyazine

Low

High

Low

Thioridazine

100

Low

High

Moderate Perphenazine

Moderate Moderate

Low

High

Trifluoperazine

High

Low

Thiotheixene

High

Low

Fluphenazine

High

Low

Haloperidol

High

Low

Pimozide

0.5

High

Moderate

Sulpiride

200

Low

Moderate

Low

Typical / conventional

antipsychotics

Comparison of representative antipsychotics

Drug

Advantages

Disadvantages

Chlorpromazine

Generic, inexpensive

Many adverse effects

(esp. autonomic)

Thioridazine

Slight EPS, generic

Cardiotoxicity (QT

prolongation)

Fluphenazine

Generic, depot

available

(?)

(?) increased tardive

increased tardive

dyskinesia

Thiothixene

(?)

(?) decreased tardive

decreased tardive

dyskinesia

Uncertain

Haloperidol

Generic, injection and

depot A/V, few

autonomic s/e

Prominent EPS

Typical / conventional

antipsychotics

Receptor blockade and Adverse effects

Receptor type

Consequence of blockade

D2 dopaminergic

Extrapyramidal symptoms; prolactin

release

H1 histaminergic

Sedation

Muscarinic cholinergic Dry mouth, blurred vision, urinary

retention, constipation, tachycardia

Alpha1-adrenergic

Orthostatic hypotension; reflex

tachycardia

5-HT2 serotonergic

Weight gain

Typical / conventional

antipsychotics

Adverse effects

Extrapyramidal symptoms (EPS)

Early reactions – can be managed with drugs

Acute dystonia

Parkinsonism

Akathisia

Late reaction – drug treatment unsatisfactory

Tardive dyskinesia (TD)

Early reactions occur less frequently with low potency

drugs

Risk of TD is equal with all agents

Typical / conventional

antipsychotics

Adverse effects

Acute dystonia

Develops within a few hours to 5 days after first dose

Muscle spasm of tongue, face, neck and back

Oculogyric crisis (involuntary upward deviation of eyeballs)

Opisthotonus (tetanic spasm of back muscles, causing trunk

to arch forward, while head and lower limbs are thrust

backwards)

Laryngeal dystonia can impair respiration

Management

Anticholinergics (Benztropine, diphenhydramine IM/IV)

Lower or split dosing

Switch agent

Add scheduled benztropine / diphenhydramine with

antipsychotic

Typical / conventional

antipsychotics

Adverse effects

Parkinsonism (neuroleptic induced)

Occurs within first month of therapy

Bradykinesia, mask-like facies, drooling, tremor,

rigidity, shuffling gait, cogwheeling, stooped posture

Shares same symptoms with Parkinson’s disease

Management

Centrally acting anticholinergics (scheduled benztropine

/ diphenhydramine / benzhexol with antipsychotics) and

amantadine

Avoid levodopa as it may counteract antipsychotic

effects

Switch to atypical antipsychotics for severe symptoms

Typical / conventional

antipsychotics

Adverse effects

Akathisia

Develop within first 2 months of therapy

Compulsive, restless movement

Symptoms of anxiety, agitation

Management

Beta blockers (propranolol)

Benzodiazepines (e.g. lorazepam)

Anticholinergics (e.g. benztropine, benzhexol)

Reduce antipsychotic dosage or switch to low potency

agent

Typical / conventional

antipsychotics

Adverse effects

Tardive dyskinesia (TD)

Develops months to years after therapy

Involuntary choreoathetoid (twisting, writhing,

worm-like) movements of tongue and face

Can interfere with chewing, swallowing and

speaking

Symptoms are usually irreversible

Typical / conventional

antipsychotics

Adverse effects

Tardive dyskinesia (TD)

Management

Some manufacturers suggest drug withdrawal at earliest

signs of TD (fine vermicular movements of tongue) may

halt its full development

Gradual drug withdrawal (to avoid dyskinesia)

Use lowest effective dose

Atypical antypsychotic for mild TD

Clozapine for severe, distressing TD

Inconsistent results with

Diazepam, clonazepam, valproate

Propranolol, clonidine

Vitamin E

Typical / conventional

antipsychotics

Other Adverse effects

Neuroleptic malignant syndrome (NMS)

Rare but serious reaction, 0.2% of patients on

neuroleptics

High fever, autonomic instability, mental status

changes, leaden rigidity, elevated CK, WBC,

myoglobinuria

Management

Discontinue antipsychotic

Paracetamol for hyperthermia

IV fluids for hydration

Benzodiazepines for anxiety

Dantrolene for rigidity and hyperthermia

Bromocriptine for CNS toxicity

Typical / conventional

antipsychotics

Other Adverse effects

Neuroleptic malignant syndrome (NMS)

After symptom resolution

Some suggest to wait for at least 2 weeks before

resuming

Use lowest effective dose

Avoid high potency agents

Consider atypical antipsychotics

However, NMS has been reported from

patients taking clozapine, risperidone,

olanzapine and quetiapine

Typical / conventional

antipsychotics

Other Adverse effects

Prolactinemia

D2 receptor blockade decreases dopamine inhibition of

prolactin

Results in galactorrhea, amenorrhea, loss of libido

Managed with bromocriptine

Sedation

Administer once daily at bedtime

Seizures

Haloperidol has a lower risk of seizures

Anticonvulsants (beware or possible interaction with

antipsychotic)

Atypical antipsychotics

Refers to newer agents

Also known as

“Serotonin-dopamine antagonists”

Postsynaptic effects at 5-HT2A and D2

receptors

Atypical antipsychotics

Mechanism of action

Similar blocking effect on D2 receptors

Seem to be a little more selective, targeting the

intended pathway to a larger degree than the

others

Also block or partially block serotonin receptors

(particularly 5HT2A, C and 5HT1A receptors)

Aripiprazole: dopamine partial agonist (novel

mechanism)

Atypical antipsychotics

Properties

Available evidence to show advantage for

some (clozapine, risperidone, olanzapine)

but not all atypicals when compared with

typicals

At least as effective as typicals for

positive symptoms

May be more efficacious for negative and

cognitive symptoms (still under debate)

Atypical antipsychotics

Properties

Less frequently associated with EPS

More risk of weight gain, new onset

diabetes, hyperlipidemia

Novel agents, more expensive

Atypical antipsychotics

Potency

All atypical antipsychotics are equally

effective at therapeutic doses

Except clozapine

Most effective antipsychotic

For resistant schizophrenia

line due to life-threatening side effect

Atypical antipsychotics

Relative receptor

Relative receptor--binding of atypical antipsychotics

binding of atypical antipsychotics

Drug

D11

D22

55--HT

HT22

a11

M11

H11

Clozapine

+++

+++ +++

+++ +

Risperidone

+++

+++ +++

+++

+++ --

Olanzapine

+++

+++ ++

Quetiapine

+++

+++ +

Ziprasidone

+/--

+++

Aripiprazole

+++

+++ ++

Atypical antipsychotics

Comparison of representative atypical antipsychotics

Drug

Advantages

Disadvantages

Clozapine

For treatment

For treatment--resistant cases,

resistant cases,

little EPS

Risk of fatal agranulocytosis

Risperidone

Broad efficacy, little or no EPS

at low doses

EPS and hypotension at high

doses

Olanzapine

Effective with positive and

negative symptoms, little or

no EPS

Weight gain

Quetiapine

Similar to risperidone, maybe

less weight gain

Dose adjustment with associated

hypotension, bd dosing

Ziprasidone

Perhaps less weight gain than

clozapine, Inj A/V

QT prolongation

Aripiprazole

Less weight gain, novel

mechanism potential

Uncertain

Atypical antipsychotics

Relative incidence of Adverse effects

Drugs

Sedatio

Sedatio
nn

EPS

EPS Anticholinergic

Anticholinergic

Orthostasis

Orthostasis Seizure

Seizure

Prolactin

Prolactin
elevation

elevation

Weight

Weight
gain

gain

Clozapine

++++

Risperidone

+++

0 to

++++

Olanzapine

+++

Quetiapine

+++

Ziprasidone

Aripiprazole

Atypical antipsychotics

line atypical antipsychotics

All atypicals except clozapine

NICE recommendations

Atypical antipsychotics considered when choosing 1

line treatment of newly diagnosed schizophrenia

Treatment option of choice for managing acute

schizophrenic episode

Considered when suffering unacceptable Adverse

effects from a conventional antipsychotic

Changing to an atypical not necessary if typical

controls symptoms adequately and no unacceptable

Adverse effects

Atypical antipsychotics

line atypical antipsychotic

Clozapine

Most effective antipsychotic for reducing symptoms

and preventing relapse

Use of clozapine effectively reduce suicide risk

1% risk of potentially fatal agranulocytosis

Acute pronounced leukopenia with great reduction in

number of neutrophil

Clozapine should be introduced if schizophrenia is

inadequately controlled despite sequential use of 2 or

more antipsychotic (one of which should be an atypical)

each for at least 6-8 weeks)

Atypical antipsychotics

Clozapine

Rare cases of myocarditis and cardiomyopathy

Fatal

Most commonly in first 2 months

CSM recommendations

Physical exam and medical history before starting

Persistent tachycardia esp. in first 2 weeks should

prompt observation for cardiomyopathy

If myocarditis or cardiomyopathy, stop clozapine

Inform patients for unexplained fatigue, dyspnea,

tachypnea, chest pain, paipitation and ask them to

report these signs and symptoms immediately

Non

Non--antipsychotic agents

antipsychotic agents

Benzodiazepines

Useful in some studies for anxiety, agitation,

global impairment and psychosis

Schizophrenic patients are prone to BZD abuse

Limit use to short trials (2-4 weeks) for

management of severe agitation and anxiety

Lithium

Limited role in schizophrenia monotherapy

Improve psychosis, depression, excitement, and

irritability when used with antipsychotic in some

studies