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ANTIDEPRESSANTSANTIMANIAC DRUGSCNS STIMULANTS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

They are among the most commonly prescribed drugs .Depression: It is a the most commonly serious disorder of

mood, ranges from mild to very serious condition Types of Depression - Two types

Unipolar Exogenous / Reactive Depression Endogenous/Major Depression (MDD) Bipolar

Antidepressant Drugs

Antidepressant Classes

1. Selective Serotonin Reuptake Inhibitor (SSRI)• Sertraline, Fluoxetine• Paroxetine, Citalopram, Escitalopram

2. Tricyclic Antidepressant (TCA)• Amitriptyline, Nortriptyline • Imipramine, Desipramine• Doxepine, Trimipramine

Antidepressant Classes

MAO Inhibitors Phenelzine, moclobemide Tranylcypromine Atypical Antidepressants Bupropion, nefazodone, mianserin, Trazodone, venlafaxine Mirtazepine

Tricyclics

Amitryptyline Potent sedative Weight gain ++ Anticholinergic ++ Most researched 150mg / day(Therapeutic in 95%

of adults)

Clomipramine Similar side effects

to amitryptyline. Said to be best for

obsessional symptoms.

150mg / day

MOA of TCAs

Depression is due to deficiency of nor-epinephrine & serotonin

Normally action of released NE & serotonin is terminated by active reuptake into the nerve terminal from the synapse via specific transporters.

TCAs block the amine transporters (uptake pumps) for nor-epinephrine (NET) & serotonin (SERT) in brain.

Facilitation of NE & serotonin transmission ---- improves symptoms of depression .

Tricyclics

Imipramine Stimulant Anticholinergic ++ 150 mg/ day

Dothiepin Sedative Same side effects as

amitryptyline. By far and away the

most toxic antidepressant.

150 mg / day

Side effects of TCA’s

antimuscarinic effects postural hypotension tachycardia, arrhythmias sedation weight gain jittery feeling sexual dysfunction (ejaculatory)

SSRI

Citalopram Few interactions

Most expensive

20 mg /day

Fluoxetine Sedation –Skin s/e

Anxiety +Cheapest

20-80 mg /day

Fluvoxamine Gut s/e + Insomnia - 200 mg /day

Paroxetine Sedation + Withdrawal problems ?

20 mg /day

Sertraline Diarrhoea 50 mg /day

SSRI

First choice in elderly.

First choice if heart disease.

First choice if suicide risk.

More expensive.

Side effects Like TCA reduce

with time. Gut problems

predominate. Flat dose response

curve – so no need to titrate dose upwards.?

Duloxetine, Desvenlafaxine, Milnacipran

MOA: Inhibit Serotonin& NE reuptake at all doses by

binding to NET & SERTVenlafaxine: Potent inhibitor of serotonin reuptake & at

medium to high doses. Inhibitor of NE reuptake. Weak Dopamine re-uptake inhibitor at higher

doses.No effect on muscarinic, adrenergic or histaminic receptors.

So they are preferred over TCAs for MDD & pain syndromes.

MAOI The old ones block peripheral MAOI ( B )

and central MAOI (A) so a low tyramine diet is needed. ? Obsolete.

Moclobemide. Only MAOI-A. Special place in anxiety disorder. 300-600mg / day.

Atypical antidepressants

Trazodone. Unique structure. Low cardiotoxicity, few anticholinergic side

effects. Drowsiness +. Nausea. 150 mg /day.

Atypical antidepressants

Mirtazapine : Blocks 5HT2 , & presynaptic α2 receptors.Enhances release of Serotonin & NEAmoxapine: Potent Nor-Epinephrine uptake inhibitor but

mild inhibition of Serotonin reuptake. Blocks D2 receptors

Bupropion: Inhibitor of NE reuptake, Weak Inhibitor of dopamine reuptake

Maprotiline: Potent Nor-Epinephrine uptake inhibitor.

Therapeutic Uses

All are useful in Major depression, in combination with other drugs.

Bupropion is useful in ADHD Bupropion also helps in reducing craving &

attenuating the withdrawal symptoms for Nicotine in tobacco users trying to quit smoking.

Panic attacks, post traumatic stress disorder Obsessive compulsive disorder Nocturnal enuresis Premenstrual syndrome Chronic alcoholism

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Bipolar Disorder:Symptom DomainsManiaEuphoriaGrandiosityPressured speechImpulsivityExcessive libidoRecklessnessDiminished need for sleep

DepressionDepressionAnxietyIrritabilityHostilityViolence or suicide

Manic, depressed or mixed

Psychosis•Delusions•Hallucinations•Sensory hyperactivity

Cognition•Racing thoughts•Distractability•Poor insight•Disorganization•Inattentiveness•Confusion

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Mood Disorders:Therapeutic Options

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Lithium* (A, M)

Anticonvulsants

Valproate* (A)

Lamotrigine* (M)

Carbamazepine (A)

Oxcarbazepine*

Topiramate

Gabapentin

Psychotherapy

Cognitive behavioral therapy Marital/family counseling

Interpersonal therapy Group therapy

Pharmacological/Somatic

Antidepressants; OLZ/FLU* (D)

Quetiapine* (D)

Electroconvulsive therapy

Possibly:» Bright light therapy» Transcranial magnetic stimulation » Vagal nerve stimulation» Sleep deprivation

First generation antipsychotics

Second generation antipsychotics

Clozapine

Olanzapine* (A, M)

Risperidone* (A)

Quetiapine* (A)

Ziprasidone* (A)

Aripiprazole* (A)

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Mood Stabilizer PharmacokineticsDrug Desired

CpDistribution Metabolism Elimination

Lithium 0.6-1.0 mEq/L

No PBkidneys, thyroid

None Renally,18-20 hours

CBZ 6-12 mcg/ml

Complete Hepatic,Autoinducer10,11 epoxide

15-28 hours

VPA 50-120 mcg/ml

Rapid in CNS

Hepatic, Inhibitor or Inducer

8-17 hours

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LITHIUM

Narrow therapeutic index Slow onset of action Numerous adverse effects

DISADVANTAGES

BIPOLAR DISORDER

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Factors Affecting Lithium Cp

Impaired Renal Function Pregnancy Sodium balance Medications

Diuretics → Na depletion → Li reabsorption

Caffeine ↓ lithium levels ACE Inhibitors → ↓ GFR → increase Li

concentration

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Lithium: Adverse EffectsOrgan System Clinical Presentation Comments

Cardiovascular ECG changes T wave suppression, delayed or irregular rhythm, increase in PVCsSick sinus node syndrome (SSNS)Myocarditis

Dermatologic AcnePsoriasisRashes

WorsensTreatment-refractory worseningMaculopapular and follicular

Endocrine Hypothyroid state About 5% goiter; about 4% clinically significant hypothyroidism

Hyperparathyroid state Clinically nonsignificant

Fetus (teratogenic) Tricuspid valve malformationAtrial septal defect

Ebstein’s anomaly

Gastrointestinal AnorexiaNausea (10-30%)VomitingDiarrhea (5-20%)

Usually early in treatment and usually transient; may be early sign of toxicity

Slow release preparations may help

Hematological Granulocytosis May be useful in disorders such as Felty’s syndrome, iatrogenic neutropenia. May counter CBZ-induced leukopenia

Renal Polyuria-polydipsia (Nephrogenic diabetes insipidus)

May be an indication of morphologic changesRequires adequate hydration

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Neurological Cognitive; tremors

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Valproic Acid Pharmacokinetics Usually inhibits hepatic metabolism Occasionally induces hepatic

metabolism

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VALPROATE

Adverse effects Weight gain Tremors Hyperammonemia PCOS (?)

DISADVANTAGES

BIPOLAR DISORDER

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Pancreatitis

Hepatotoxicity

Teratogenicity

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CBZ Pharmacokinetics

Oxidation to CBZ-10,11-epoxide Potent enzyme inducer

antidepressants, anticonvulsants, antipsychotics

Autoinduction serum level should stabilize within 4

weeks

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LAMOTRIGINE

Slow titration to avoid rash Adverse effects

Serious rashes▪ SJS▪ TEN

BIPOLAR DISORDER

DISADVANTAGES

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CNS Stimulants

Have predominantly stimulant effect onthe central nervous system

Convulsants and respiratory stimulants Psychomotor stimulants Hallucinogens

CONVULSANTS AND RESPIRATORY STIMULANTS

Little effect on mental function

Act mainly on the brain stem and spinal cord

Higher dosage causes convulsions

Sometimes called analeptics

Picrotoxin

Obtained from the fishberry also blocks the action of GABA on chloride channels

Doxapram

Similar to the above drugs Bigger margin of safety between

respiratory stimulation and convulsions

Causes nausea, coughing and restlessness, which limit its usefulness

Occasionally used as an intravenous infusion in patients with acute respiratory

PSYCHOMOTOR STIMULANTS

Cause excitement and euphoria Decrease feelings of fatigue Increase motor activity

Psychomotor Stimulants

Methylxnthines Nicotine Methylphenidate Cocaine Amphetamine Vareneciline

Methylxanthines

Theophylline (tea)Theobromine (cocoa)Caffeine

Caffeine, the most widely consumed stimulant in the

world,is found in highest concentration in coffee

Also present in tea, cola drinks, chocolatecandy, and cocoa.

Mechanism of action

Translocation of extracellular calcium

Increase in CAMP and CGMP caused by inhibition of phosphodiesterase

Blockade of adenosine receptors

Therapeutic uses:

Cocaine has a local anesthetic Applied topically as a local anesthetic

during eye, ear, nose, and throat surgery Local anesthetic action due to a block of

voltage-activated sodium channels Only local anesthetic that causes

vasoconstriction. This effect is responsible for necrosis

Perforation of the nasal septum is seen with chronic inhalation of cocaine powder