•Antidepressant

•Antipsychotics (neuroleptics)

•Mood stabilizers.

•Drugs for anxiety and sleep disorders.

Following drug groups are considered

ANTIDEPRESSANT AGENTS

CHEMISTRY

A variety of different chemical

structures have been found to

have antidepressant activity.

BASIC PHARMACOLOGY OF

ANTIDEPRESSANTS

A. Tricyclics

Imipromine and amitriptyline

are prototypical drugs of the

class.

B. Heterocyclics, second

generation drugs

Amoxapine and maprotiline

resemble the structure of the

tricyclic agents, while trazodone

and bupropion are distinctive.

Venlafaxine is a newe.

C. Selective serotonin reuptake

inhibitors (SSRI)

The antimuscarinic,

antihistaminic, and alpha

adreneaceptor-blocking

actions of tricyclic

antidepressant contribute only

to the toxicity of these agents.

Fluoxetine, antidepressant

with minimal autonomic

toxicity, a highly selective

serotonin reuptake inhibitor.

Three selective serotonin

reuptake inhibitor : (1)

paroxetine (2) sertraline (3)

fluvaxamine.

D. Monoamine oxidase (MAO) inhibitors

MAO inhibitors may be classified as hydrazides, exemplified by the C-N-N moiety, as in the case of phenelzine and isocarboxazid; or nonhydrozides.

Tranycypromine a weak inhibitor of MAO.

Tranycypromine retains some of the sympthomimetic characteristic of the amphetamines.

Older MAO inhibitors nonselective inhibitors of both MAO-A and MAO-B.

Moclobemide is a new, short-acting, selective MAO-A inhibitor.

E. Sympthomimetic stimulants

Dextroamphetamine, other

amphetamines, and

amphetamine surrogates such

as methylphenidate

occasionally used ad

antidepressants.

PHARMACOKINETICS

A. Tricyclics

Most tricylics incompletely

absorbed and undergo

signigicant first-pass

metabolism.

High protein binding and relatively high lipid solubility volumes of distribution very large.

Tricylics metabolized by two major routes : transformation of the tricylics nucleus and alteration of the aliphatic side chain.

B. Heterocyclics

The pharmacokinetics of these drugs and of the tricyclics similar variable bioavailability, high protein binding, variable and large volumes of distribution, active metabolites.

Trazodone and venlafaxine shortest plasma half-lives.

C. Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine well absorbed, and peak plasma concentrations within 4-8 hours.

Its demethylated active metabolite, norfluoxetine half-life of 7-9 days at steady state; a slightly shorter half-life.

Fluoxetine inhibits various drug-metabolizing enzymes a number of significant drug-drug interactions with other antidepressants and with other drugs as well.

Sertraline and paroxetine pharmacokinetic parameters similar to those of tricyclics.

D. MAO inhibitors

MAO inhibitors readily absorbed from the gastrointestinal tract.

Hydrazide inhibitors (phenelzine and isocarboxazid) are acetylated in the liver and manifest differences in elimination depending on the acetylation phenotype of the individual.

The effect persist for from 7 days (tranycypromine) to 2 or 3 weeks (phenelzine, isocarbonazid) after discontinuance of the drug.

Moclobemide is rapidly absorbed and excreted, with over 90% of the drug appearing a metabolites in the urine within 12 hours.

MECHANISM OF ACTION

The monoamine hypothesis

propopse in depression

deficiency of the

neurotransmitters

nonadrenaline and serotonin in

the brain can be altered by

antidepressants.

Drugs affects depression modify amine storage, release, or uptake concentration of amines in nerve endings and/or at postsynaptic receptors is enhanced.

Specific serotonin reuptake inhibitors preventing serotonin reuptake and have more limited effects on nonadrenaline reuptake.

Tricylclic antidepressants

inhibit noradrenaline

reuptake, but effects on

serotonin reuptake vary

widely; desipramine and

protriptyline minimal

potential for raising,

serotonin concentration.

MAO inhibitors block a major

degradative pathway for the

amine neurotransmitters

permits more amines to

accumulate in presynaptic

and more to be released.

Table. Pharmacokinetic parameters of various antidepressants

Drug Bioavailability (%)

Protein binding (%)

Plasma t1/2 (hours)

Active metabolites Volume of distribution

(1/kg)

Therapeutic plasma concentrations

(ng/mL)

Amitriptyline 31-61 82-96 31-46 Nortriptyline 5-10 80-200 total

Amoxapine No data No data 8 7-8-Hydroxy No data No data

Bupropion 60-80 85 11-14 ? 20-30 25-100

Clomipramine No data No data 22-84 Desmethyl 7-20 240-700

Desipramine 60-70 73-90 14-62 No data 22-59 1452

Doxepin 13-45 No data 8-24 Desmethyl 9-33 30-150

Flouxetine 70 94 24-96 Norfluoxetine 12-97 No data

Imipramine 29-77 76-95 9-24 Desipramine 15-30 > 180 total

Maprotiline 66-75 88 21-52 Desmethyl 15-28 200-300

Nortriptyline 32-79 93-95 18-93 10-Hydroxy 21-57 50-150

Paroxeline 50 95 24 None 28-31 No data

Protriptyline 77-93 90-95 54-198 No data 19-57 70-170

Sertraline No data 98 22-35 Desmethyl 20 No data

Trazodone No data No data 4-9 m-Chlorophenyl-piperazine

No data No data

CLINICAL INDICATIONS

A.Depression.

B.Panic disorder.

C.Obsessive-compulsive disorders.

D.Enuresis.

E.Chronic pain.

DRUGS CHOICE

Antidepressant drugs are apt

most successful in patients

with”vegetative”

characteristics, including

psychomotor retardation, sleep

disturbance, poor appetite and

weight loss, and loss of libido.

DOSAGE

Table. Usual daily doses of antidepressant drugs__________________________________________Drug Dose (mg)__________________________________________Tricylics

Amitriptyline 75-200Clomipramine 75-300Desipramine 75-200Doxepin 75-300Imipramine 75-200Nortriptyline 75-150Protriptyline 20-40Trimipramine 75-200

__________________________________________

DOSAGE

__________________________________________

Drug Dose (mg)

__________________________________________

Second generation drugs

Amoxapine 150-300

Bupropion 200-400

Maprotiline 75-300

Trazodone 50-600

Venlafaxine 75-225

__________________________________________

DOSAGE

__________________________________________Drug Dose (mg)__________________________________________Monoamine oxidase inhibitors

Isocarboxazid 20-50Phenelzine 45-75Tranylcypromine 10-30

Selective serotonin reuptake inhibitorsFluoxetine 10-60Paroxetine 20-50Sertraline 50-200

__________________________________________

ADVERSE EFFECTS

A. Tricyclic antidepressant

Unwanted effect antimuscarinic action, i.e. dry mouth (predisposing to tooth decay), blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated), bladder neck obstruction (may lead yo urinary retention in older males).

Postural hypotension, interference with sexual function, weight gain, prolongation of the QT interval of the ECG.

Some TCAs (especially trimipramine and amitriptyline) heavily sedating through combination of antihistaminergic and -adrenergic blocking actions.

Clinical features of overdose

(1) antimuscarinic effect (2)

consciousness (3) respiration

depression (4) hypothermia (5)

neurological signs include

hyperreflexia, myoclonus and

divergent strabismues. Extensor

plantar responses (6) sinus

tachycardia.

B. Selective serotonin reuptake

inhibitors

Unwanted effects nausea,

anorexia, dizziness,

gastrointestinal disturbance,

agitation, akathisia, (motor

restlessness) and anorgasmia

(failure to experience an orgasm).

Disrupt the pattern of sleep with increased awakenings, transient reduction in the amount of REM and increased REM latency but eventually sleep improves due to elevation of mood.

The serotonin syndrome restlessness, tremor, shivering and myoclonus possibly on to convulsions, coma and death.

C. Monoamine oxide inhibitors

Adverse effect postural

hypotension (especially in

elderly) and dizziness.

Less common headache, irritability, apathy, insomnia, fatigue, ataxia, gastrointestinal disturbances including dry mouth and constipation, sexual dysfunction (especially anorgasmis), blurred vision, difficult micturition, sweating, peripheral, oedema, tremulousness, restlessness, and hyperthermia.Appetite may increase inappropriately, causing weight gain.

INTERACTIONS

A. TCAs and SSRIs

Pharmacodynamic interaction : TCAs cause sedation and co-prescription with other sedative agents such as opioid analgesics, antihistamines, anxiolytics, hypnotics and alcohol excessive drowsiness and daytime somnolence.

Risk of QT prolongation with

many other cardiovascular drugs.

TCAs and SSRIs central

nervous system toxicity of co-

prescribed with the dopaminergic

drugs entacapone and selegiline

(for Parkinson’s disease).

SSRIs increase the risk of toxicity

when combined with other drugs

which upregulate serotonin

transmission.

Tricyclics and SSRIs lower the

convulsion threshold epilepsy more

difficult to control by anti-epilepsy

drugs and lengthening seizure time

in electroconvulsive therapy.

Pharmacokinetic

interactions : TCAs and

SSRIs metabolised

extensively by cytochrome

P450 enzymes.

Table. Psychotropic (and selected other) drugs known to be CYP 2D6 substrates and inhibitors

CYP 2D6 inhibitorsAntidepressants.ParoxetineFluoxetine

CYP 2D6 substratesAntidepressants Antipsychotics MiscellaneousParoxetine Chlorpromazine DexfenfluramineFluoxetine Haloperidol OpioidsCitalopram Thioridazine CodeineSertraline Zuclapenthixol Hydrocodeinevenlafaxine Perphenazine DihydrocodeineAmitriptyline Risperidone TramadololClomipramine Ethyl morphineDesipramine TenamfetamineImipramine (‘ecstasy’)Nortriptyline Bupropion

-blockersPropanololMetoprololTimololBufaralol

Table. Psychotropic (and selected other) drugs known to be CYP 3A4 substrates, inhibitors and inducers

CYP 3A4 inhibitorsAntidepressants Other drugsNefazodone CimetidineFluoxetine Erythromycin

Ketoconazole(and grapefruit juice)

CYP 3A4 substratesAntidepressants Anxiolytics, hypnotics Miscellaneous

and antipsychoticsFluoxetine Alprazolam BuprenorphineSertraline Buspirone CarbamazepineAmitriptyline Diazepam CortisolImipramine Midazolam DexamethasoneNortriptyline Triazolam TestosteroneTrazodone Zopiclone Calcium chanel blockers

Haloperidol DiltiazemNifedipineAmlodipine

Other drugsAmiodaroneOmeprazoleOral contraceptivesSimvastatin

CYP 3A4 inducersAntidepressants MiscellaneousSt. John’s Wort Carbamazepine

PhenobarbitalPhenytoin

B. Monoamine oxidase inhibitors

Sympathomimetic substances

highly dangerous hypertensive

reactions if taken by patient

using MAC inhibitors.

ANTIPSYCHOTIC AGENTS

The terms antipsychotic ––

a group of drugs that have

been used mainly for

treating schizophrenia.

CHEMICAL TYPES

The drugs can be classified into

several groups.

BASIC PHARMACOLOGY OF

ANTIPSYCHOTIC AGENTS

A. Phenothiazine Derivatives

Three subfamilies of

phenothiazines (1) Aliphatic

derivatives [eg.chlorpromazine]

(2) Piperidine derivatives

[eg.thiodazine] (3) Piperazine

derivatives.

B. Thioxanthene Derivatives

C. Butyrophenone Derivatives.

D. Miscellaneous Structures : • Diphenylbutylpiperidines

(pimozide).

• Dihyroindolones (molindone).

• Dibenzoxazepines (loxapine).

• Dibenzodiasepines (clozapine).

• Benzamides (remoxipride).

PHARMACOKINETICS

A. Absorption & Distribution

Most antipsychotic drugs are

readily but incompletely

absorbed.

Many of these drugs undego

significany first-pass

metabolism.

Oral doses of chlorpromazine

and thioridazine, haloperidol,

which is less likely to be

metabolized, has an average

systemic availability of about

65%.

Highly lipid-soluble, protein-

bound (93-99%).

Metabolites of chlorpromizine

may be excreted in the urine

weeks after the last dose.

B. Metabolism.

Almost completely metabolized

by a variety of processes.

C. Excretion.

Elimination half-lives vary from

10-24 hours.

PHARMACOLOGIC EFFECTS

The first phenothiazine

antipsychotic drugs, with

chlorpromazine as the

prototype, proved to have a wide

variety of CNS, autonomic, and

endocrine effects.

These actions were traced to

blocking effects at a remarkable

number of receptors.

These include dopamine and

alpha-adrenoceptor, muscarinie,

H1 histaminic and serotonin (5-

HT2) receptors.

A. Dopaminergic systemic.

After dopamine was recognized

as a neurotransmitter, various

experiments showed that its

effects on production of cAMP

by adenylyl cyclase could be

blocked by most antipsychotic

drugs.

Antipsychotic action is now

though to be produced by their

ability to block dopamine in the

mesolimbic and mesofrontal

systems.

B. Dopamine Receptors and

Their Effects.

At present, five different

dopamine receptors have been

described, consisting of two

separate families, the D1-like and

D2-like receptor groups.

The D1 receptor is coded by a

gene on chromosome 5,

increases cAMP by activation of

adelylyl cyclase, and is located

mainly in the putamen, nucleus

accumbens, and olfactory

tubercle.

The second member of this

family, D5, is coded a gene on

chromosome 4, also

increases cAMP, and is found

in the hypocampus and

hypothalamus.

C. Differences Among

Antipsychotic Drugs.

Although all effective

antipsychotic drugs block D2

receptors, the degree of this

blockade in relation to other

actions on receptors varies

considerably between drugs.

D. Neurophysiologic Effects.

Antipsychotic drugs produce

shifts in the patient of

electroencephalographic,

frequencies.

The slowing (hypersynchrony) is

sometimes focal or unilateral,

which.

E. Endocrine Effects.

Amenorrhea-galactorrhea, false-

positive pregnancy tests, and

increased libido have been

reported in women, whereas men

have experienced decreased

libido & gynecomastia.

F. Cardiovascular Effects.

Orthostatic hypotension and high

resting pulse rates frequently

result from use of the “high dose”

(low potency) phenothiazines.

Mean arterial pressur, peripheral

resistance, and stroke volume are

decreased.

INDICATION

A. Psychiatric Indications.

Schizophrenia is the primary

indication for these drugs.

CLINICAL PHARMACOLOGY OF

ANTIPSYCHOTIC AGENTS

Other psychiatric indications for

the use of antipsychotics include

Tourette’s syndrome and the

need to control disturbed

behavior in patients with senile

dementia of the Alzheimer type.

Antipsychotics in small

doses have been promoted

for the relief of anxiety

associated with minor

emotional disorders.

B. Nonpsychiatric Indications

Most antipsychotic drugs, a

strong antiemetic effect.

DOSAGE

The range of effective dosage

among various antipsychotics is

quite broad.

Patients who fail to respond to

one drug may respond to

another.

ADVERSE REACTIONS

A. Behavioral Effects.

A “pseudodepression” that may be due to drug-induced akinesia usually responds to treatment with antiparkinsonism.

Toxic-confusional states may occur.

B. Neurologic Effects.

Extrapyramidal reactions occuring early during treatment include typical Parkinson’s syndrome, akathisia (uncontrollable restlessness), and acute dystonic reactions (spastic retrocollis or torticollis), tardive dyskinesia, seizures.

C. Autonomic Nervous System Effects.

Most patients become tolerant to antimuscarinic adverse effects of antipsychotic drugs.

Orthostatic hypotension or impaired ejaculation – common complications of therapy with chlorpromazine or mesoridazine-should.

D. Metabolic and Endocrine

Effects.

Hyperprolactinemia in women

results in the amenorrhea-

galactorrhea syndrome and

infertility; in men, loss of libido,

importance, and infertility may

results.

E. Toxic or Allergic Reactions.

Agranulocytosis, cholestatic

jaundice, and skin eruptions

occur rarely with the high-

potency antipsychotic drugs

currently used.

F. Ocular Complications.

Deposits in the anterior

portion of the eye (cornea and

lens) are a common

complication of

chlorpromazine therapy.

G. Cardiac Toxicity.

Thioridazine in dose exceeding

300 mg daily is almost always

associated with minor

abnormalities of T waves.

H. Use in Pregnancy;

Dysmorphogenesis.

I. Neuroleptic Malignant

Syndrome.

MOOD STABILISERS

Mode of action not fully

understood.

Main effect inhibit hydrolysis

of inositol phosphate reducing

the recycling free inositol for

synthesis of

phosphatidylinositides.

LITHIUM

Pharmacokinetics

Therapeutic plasma concentration

close to the toxic concentration

(low therapeutic index).

Orally rapidly absorbed.

Peak plasma lithium concentration

5 h.

Distributed throughout the

total body water higher

concentration in brain, bones

and thyroid gland.

Filtered by the glomerulus,

80% is reabsorbed by the

proximal tubule.

Chronic use the plasma t1/2 of

lithium 15-30 h.

Lithium given 12 hourly to

avoid unnecessary fluctuation,

maintain a plasma

concentration just below the

toxic level.

A steady-state plasma

concentration 5-6 days (i.e. 5

x t1/2) in patients with normal

renal function.

Old people and patients with

impaired renal function a

longer t1/2.

Indications and Use

Lithium carbonate effective treatment in > 75% of episodes of acute mania of hypomania.

Lithium used in combinations with benzodiazepine.

For prophylaxis, lithium is indicated two episodes of mood disturbance in two years.

Adverse Effects• Fine tremor (especially involving

the fingers), constipation, polyuria and polydipsia, metallic taste in the mouth, weight gain, oedema, goitre, hypothyroidism, acne, rash, diabetes insipidus and cardiac arrhytmias. Mild cognitive and memory impairment.

• Signs of infoxication (plasma concentration greater than 1.5 mmol/1) gastrointestinal (diarrhoea, anorexia, vomiting), neurological, (blurred vision, miscle weakness, drowsiness, sluggishness, coarse tremor, leading on to giddiness, ataxia, dysarhria).

• Severe overdosage or rapid

reduction in renal clearance

hyperreflexia,

hyperextension of limbs,

convulsions, toxic

psychoses, syncope,

oliguria, coma, death.

Interactions

Drug interfere with lithium

excretion by the renal tubules

diuretics, ACE inhibitors

and angiotensin-11 antagonis,

non steroidal anti-

inflammatory analgesics.

Theophylline and sodium-

containing antacids plasma

lithium concentration.

Diltiazem, verapamil,

carbamazepine and phenytoin

neurotoxicity.

Concomitant use of thioridazine

ventricular arrhythmias.

Carbamazepine as an alternative of lithium for prophylaxis of bipolar affective disorder.

Mode of action involve anonism in inhibitory GABA transmission at the GABA-benzodiazepine receptor complex.

Carbamazepine

Valproic acid licenced for

use in the treatment of acute

mania unresponsive to

lithium.

Valproic Acid

DRUGS USED IN ANXIETY AND SLEEP

DISORDERS

Treatment

Fast-acting benzodiazepine such as alprazolam (1-3 mg/day p.o.), drug with delayed efficacy but fewer problems of withdrawal such as a TCA, e.g. clomipramine (100-250 mg/day p.o) or an SSRI, e.g. paroxetine (20-50 mg/day p.o).

PANIC DISORDER

Treatment

The drugs SSRI, paroxetine,

the MAOI, phenelzine and the

RIMA, moclobemide in the

same doses as for depression.

SOCIAL ANXIETY DISORDES

Table. Relative effectiveness of pharmacological treatments for anxiety disordes

Table. Properties of anti-anxiety drugs

Treatment is poorly researched.

Benzodiazepines, TCAs and

MAOIs; paroxetine (SSRI) (20-

50 mg/day p.o) licenced for

this indications.

POST-TRAUMATIC STRESS DISORDES

(PTSD)

Buspirone

Structurally unrelated to other

anxiolytics efficacy in GAD.

Mode of action suppresses 5HT

neurotransmission through a

selective activation of the inhibitory

presynaptic 5HT1A-receptor.

GENERALISED ANXIETY DISORDER

Buspirone a t1/2 of 7 h, metabolised

in the liver, an active metabolite that, may accumulate over weeks.

Twice daily dosing range being 15-30 mg/d p.o., max. 45 mg/d.

Adverse effect can dizziness, headache, nervousness, excitement, nausea, tachycardia and drowsiness.

The Duration of Therapy

Depends on the nature of the

underlying illness.

Paroxetine (SSRI) & Venlafaxine (SNRI)

Effective.

TCAs benefit.

DRUGS FOR INSOMNIA

Benzodiazepines

All benzodiazepines and newer

benzodiazepine safe and

effective for insomnia.

INSOMNIA

Pharmacokinetics.

Benzodiazepines effective after

administration by mouth but

enter the circulation at very

different rates that are reflected

in the speed of onset of action.

Liver metabolises usually to

inactive metabolites, some

compounds produce active

metabolites, some with long t1/2

which greatly extends drug

action.

Uses.

Benzodiazepine used for : insomnia, anxiety, alcohol withdrawal states, muscle spasm due to a variety of causes, including tetanus and cerebral spasticity, epilepsy (clonazepam), anaesthesia and sedation for endoscopies and cardioversion.

• Intravenous formulations, e.g. diazepam 10-20 mg, given at 5 mg/min into a large vein (antecubital fossa) to minimise thrombosis: the dose may be repeated once in 10 min for status epilepticus or in 4 h for severe acute anxiety or agitation.

Doses.

Oral doses as anxiolytics given with their indications :

• Intramuscular injection of

diazepam is absorbed,

slower in acting than an

oral dose.

Table. Properties of drugs used cfor insomnia

Adverse Effects.

Benzodiazepines affect memory and balance.

Paradoxical behaviour effect, perceptual disorders.

Headache, giddiness, alimentary tract upset, skin rashes and reduced libido can occur.

Extrapyramidal reaction.

Interactions.

All potentiate the effects of

alcohol, other central

depressants.

Overdose.

Benzodiazepines are

remarkably, safe in acute

overdose and the therapeutic

dose x 10.

Deaths have occurred

combination with alcohol.

• Drug treatment : effective for a short period (2-4 weeks).

• Some patients need long-term medication.

SUMMARY OF PHARMACOTHERAPY

FOR INSOMNIA

• Intermittent medication, taken only nights that symptoms occur, modern, short-acting, compound.

• Discontinuing hypotic drugs not a problem.