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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)
* FDA approved© Janicak 17
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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
© Janicak 19
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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
© Janicak 23
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
© Janicak 25
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