PHL 322 ANTIDEPRESSANTSAND MODE STABILISING DRUGS Dr. Mohamed El-Sayed

PHL 322PHL 322

ANTIDEPRESSANTS ANTIDEPRESSANTS

AND AND

MODE STABILISING DRUGSMODE STABILISING DRUGS

Dr. Mohamed El-SayedDr. Mohamed El-Sayed

DEPRESSIONDEPRESSION

DEPRESSIONDEPRESSION

"Depression" is a very common psychiatric disorder that is related to the "mood" (affective disorder).

Depression is the most common of the affective Depression is the most common of the affective disorders (disorders (Changes in mood associated with depression and/or mania)

Disorders of MOODDisorders of MOOD rather than disturbance in rather than disturbance in thought or cognitionthought or cognition

Clinical depression: feeling sad for more than two weeks.

Symptoms of DepressionSymptoms of Depression

1- Emotional Symptoms:1- Emotional Symptoms:

Misery and apathyMisery and apathy Loss of self esteem: feeling of guilt and Loss of self esteem: feeling of guilt and

uglinessugliness Indecisiveness and loss of motivationIndecisiveness and loss of motivation Decreased moodDecreased mood Loss of energy and interestLoss of energy and interest Feelings of hopelessness, helplessness, Feelings of hopelessness, helplessness,

guilt and anxietyguilt and anxiety

2- Biological symptoms:2- Biological symptoms:

1- Retardation of thought and action1- Retardation of thought and action

2- Loss of libido2- Loss of libido

3- loss of appetite and sleep disturbance3- loss of appetite and sleep disturbance

*** DEPRESSION IS THE MOST COMMON CAUSE OF*** DEPRESSION IS THE MOST COMMON CAUSE OF

SUICIDESUICIDE

Symptoms of "mania" are exactly the opposite:

• Excessive enthusiasm

• Self-confidence

• Mental alertness

• Rapid thought and speech

• Hyperactivity

• Irritability

• Impatience

• Aggression

Classification of DepressionClassification of Depression

A) According to number of symptoms and A) According to number of symptoms and degree:degree:

1. Mild depression-1. Mild depression----------self-limiting---------self-limiting

2. Moderate depression-2. Moderate depression--------difficulties at-------difficulties at

home and workhome and work

3. Severe depression-3. Severe depression---------serious,--------serious,

associated with suicidal thoughtsassociated with suicidal thoughts

B) According to typeB) According to type

1.1. Unipolar depression (major depression):Unipolar depression (major depression): The patient swings between "normal mood" and "depression".

- Repeated episodes of depression- Repeated episodes of depression- Mood returns to normal at the end of episode- Mood returns to normal at the end of episode- Common (75 % of cases)- Common (75 % of cases)- Non-familial- Non-familial- Associated with stressful life-events- Associated with stressful life-events- Reactive depression- Reactive depression

2- Endogenous depression2- Endogenous depression- Less common (25 % of cases)- Less common (25 % of cases)- Familial- Familial- Unrelated to external stress- Unrelated to external stress

3. Bipolar depression (manic-depressive)3. Bipolar depression (manic-depressive)

The patient swings between "mania" and

"depression“ (manic-depressive illness).

- It is mainly hereditary and appears

in early adult life.

- Alternating depression and mania- Alternating depression and mania

- both depression and mania occur

• Depression (unipolar depression)

• Mania

• Manic-depression (bipolar depression)

• Reactive depression (75%)

• Endogenous depression (25%)

What are the possible mechanisms of depression?

• Depression is associated with insufficient central release of NA and 5-HT.

• Led to development of the Biogenic Amine Hypothesis.

Disorders of Mood (Affective Disorders)Disorders of Mood (Affective Disorders)

Etiology of depression

“The monoamine theory" (proposed in 1965) suggests that depression is due to a deficiency of monoamines at certain sites in the brain, while mania is caused by an overproduction of these neurotransmitters.

However, recent biochemical studies on depressed patients do not support this theory in its simple form, since it was found that the biochemical effect of antidepressants (i.e. increasing the level of monoamines) appears very rapidly whereas their antidepressant effect takes 2-3 weeks to develop.

Therefore, it was suggested that secondary adaptive changes (but not the primary drug effect) are responsible for the clinical improvement.

Therefore, monoamines should be considered as regulators of these adaptive changes that occur in the same time as mood changes.

The Monoamine Theory of DepressionThe Monoamine Theory of Depression

Proposed in 1965 and states that Proposed in 1965 and states that DEPRESSIONDEPRESSION is caused by a functional is caused by a functional deficit of Monoamine transmitter at certain deficit of Monoamine transmitter at certain sites in the brain,sites in the brain, while MANIA results from while MANIA results from functional excess.functional excess.

The Theory is based on the ability of known The Theory is based on the ability of known antidepressat drugs (TCAs and MAOIs) to antidepressat drugs (TCAs and MAOIs) to facilitate monoaminergic transmission and of facilitate monoaminergic transmission and of drugs as drugs as ReserpinReserpine to cause depression.e to cause depression.

Pharmacological evidence supporting The Monoamine Pharmacological evidence supporting The Monoamine

Theory of DepressionTheory of Depression DrugDrug Principal actionPrincipal action Effect in depressed Effect in depressed

patientspatients

TCATCA Block NA and 5-HT Block NA and 5-HT reuptakereuptake

Increase MOODIncrease MOOD

MAO InhibitorsMAO Inhibitors Increase stores of NA Increase stores of NA and 5-HTand 5-HT


ResrpineResrpine Inhibits NA and 5-HT Inhibits NA and 5-HT storagestorage

Decrease MOODDecrease MOOD

MethyldopaMethyldopa Inhibits NA synthesisInhibits NA synthesis Decrease MOODDecrease MOOD

ECTECT Increase CNS response Increase CNS response to NA and 5-HTto NA and 5-HT


TryptophanTryptophan Increase 5-HT Increase 5-HT synthesissynthesis


Monoamine Hypothesis of DepressionMonoamine Hypothesis of Depression

Modification of Biogenic Amine HypothesisModification of Biogenic Amine Hypothesis

Antidepressantdrugs

Increased synapticconcentrations of

NA and 5-HT

Adaptive changesin the brain

Relief fromdepression

e.g. down regulation of 1- and of 2-adrenoceptors

ECT

• Antidepressant drugs downregulate 5HT2A receptors (postsynaptic).• Several post-mortem studies have shown increased 5HT2

binding in cerebrocortical tissue from depressed patients.• Nefazodone (selective 5HT2 receptor antagonist and weak inhibitor of 5HT neuronal reuptake) has antidepressant activity.

NB:1-adrenoceptorantagonists arenot antidepressant

Monoamine Receptor Hypothesis of Monoamine Receptor Hypothesis of DepressionDepression

Decrease in neurotransmitters Receptor upregulation due to lack of neurotransmitters

Normal functioning

Gene Expression Hypothesis of DepressionGene Expression Hypothesis of Depression

Brain-derived neurotrophic factor (BDNF)

Treatment of Depression

1. Psychological treatment

2. Pharmacological treatment70 % of depressed patients respond to antidepressants

3. ECT ( electroconvulsive therapy)for very severe depression, which has not responded to other treatments or for patients who cannot take antidepressants

Antidepressants Antidepressants do not act immediately (show

clinical effects after 2 weeks) indicating that secondary adaptive changes in the brain are important.

The most consistent adaptive change seen with antidepressant drugs is the downregulation of beta-, alpa-2 and 5-HT2 receptors. Alpha-1 is not affected.

Affect only people who are depressed.

Effect does not increase with increasing doses.

Antidepressants are not habit-forming.

Antidepressants differ widely in side effects.

Postulated Neurotransmitter ReceptorHypothesis of Antidepressant Action

Antidepressants introduced

Clinical effect

Postulated Adaptive Mechanisms atGene Exprerssion

AntidepressantsAntidepressants

1) 1) Tricyclics and Tetracyclics (TCAs)Tricyclics and Tetracyclics (TCAs)ImipramineImipramine Doxepin Doxepin Desipramine Amoxepine Desipramine Amoxepine TrimipramineTrimipramineMaprotilineMaprotiline Clomipramine Amitriptyline Nortriptyline Clomipramine Amitriptyline Nortriptyline ProtriptylineProtriptyline

2) 2) Monoamine Oxidase Inhibitors (MAOIs)Monoamine Oxidase Inhibitors (MAOIs)TranylcypramineTranylcypramine PhenelzinePhenelzine MoclobemideMoclobemide

3) 3) Selective Serotonin Reuptake Inhibitors (SSRIs)Selective Serotonin Reuptake Inhibitors (SSRIs)FluoxetineFluoxetine FluvoxamineFluvoxamineSertralineSertraline ParoxetineParoxetine CitalopramCitalopram

4) 4) Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)Venlafaxine Venlafaxine DuloxetineDuloxetine

5) 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)NefazodoneNefazodone TrazodoneTrazodone

6) 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)BupropionBupropion

7) 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)MirtazapineMirtazapine

8) 8) Noradrenalin Specific Reuptake Inhibitor (NRI)Noradrenalin Specific Reuptake Inhibitor (NRI)ReboxetineReboxetineTianeptineTianeptine

TRICYCLIC ANTIDEPRESSANTS (TCAs)TRICYCLIC ANTIDEPRESSANTS (TCAs)

The first tricyclic The first tricyclic antidepressant discovered antidepressant discovered was was ImipramineImipramine, which was , which was discovered accidentally in discovered accidentally in a search for a new a search for a new antipsychotic in the late antipsychotic in the late 1950s. 1950s.

Imipramine hydrochloride Imipramine hydrochloride is a member of the is a member of the dibenzazepine group of dibenzazepine group of compounds. It is compounds. It is designated 5-[3-designated 5-[3-( Dimethylamino)propyl]-( Dimethylamino)propyl]-10,11- ihydro-5H-dibenz 10,11- ihydro-5H-dibenz [b,1-azepine] [b,1-azepine] MonohydrochlorideMonohydrochloride. . Imipramine (Tofranil)

CASE PRESENTATIONCASE PRESENTATION

34 years old female resident on the Nile River, Cairo 34 years old female resident on the Nile River, Cairo Egypt. She got divorced 4 years ago. Her Teenage Egypt. She got divorced 4 years ago. Her Teenage children moved to live with father in Alexandria. Her children moved to live with father in Alexandria. Her new husband recently jailed for Narcotic trafficking. new husband recently jailed for Narcotic trafficking. She found herself alone and took complete bottle of She found herself alone and took complete bottle of unidentified tablets. unidentified tablets.

PhysicallyPhysically She was unconscious, barely breathing, She was unconscious, barely breathing, dry skin, mouth and mucous membranes, Decreased dry skin, mouth and mucous membranes, Decreased bowel sounds as well as uncontrolled muscle bowel sounds as well as uncontrolled muscle hyperactivity. hyperactivity.

Her vital signsHer vital signs showed HR 140 / min, BP 100 / 52, showed HR 140 / min, BP 100 / 52, RR 10 / min, T 41 RR 10 / min, T 41 C. C.

TRICYCLIC ANTIDEPRESSANTS (TCAs)TRICYCLIC ANTIDEPRESSANTS (TCAs)

Imipramine Desipramine Clomipramine Amitriptyline Nortriptyline Doxepin Maprotiline TrimipramineTrimipramine

MECHANISM OF ACTION of TCAs:MECHANISM OF ACTION of TCAs:

• • All tricyclics block reuptake pumps for both 5HT and NE in nerve All tricyclics block reuptake pumps for both 5HT and NE in nerve terminals by competing for binding site of the transport proteinterminals by competing for binding site of the transport protein

• • Some have more potency for inhibition of 5HT uptake Some have more potency for inhibition of 5HT uptake pumppump

clomipramine, imipramine, amitryptylineclomipramine, imipramine, amitryptyline

• • Others have more potency for inhibition of NE uptake Others have more potency for inhibition of NE uptake pumppump

nortriptyline, desipraminenortriptyline, desipramine

. . Synthesis of amines, storage and release are not directly Synthesis of amines, storage and release are not directly affected, though some TCA increase transmitter release affected, though some TCA increase transmitter release indirectly by blocking presynaptic alpha-2 adrenoreceptorsindirectly by blocking presynaptic alpha-2 adrenoreceptors

. .

- Relief of biological symptoms results from- Relief of biological symptoms results from

facilitation of NE-mediated transmissionfacilitation of NE-mediated transmission

- Relief of emotional symptoms results from - Relief of emotional symptoms results from facilitation of 5-HT-mediated transmissionfacilitation of 5-HT-mediated transmission

- TCAs (given alone) are contraindicated in manic-depressive illness, because they tend to "switch" the depressed patient to the "manic" phase, therefore, they should be combined with "lithium salts".

PHARMACOKINETICS of TCAsPHARMACOKINETICS of TCAs

Peak levels:Peak levels: 2-6 hours post ingestion 2-6 hours post ingestion

• TCAs are "lipophilic" in nature (3ry amines), therefore they are well absorbed from the GIT and readily cross the blood brain barrier to penetrate the CNS.

EliminationElimination:: hepatic oxidation hepatic oxidation

• TCAs are metabolized in the liver by demethylation (Imipramine to Desipramine, Amitriptyline to Nortriptyline) and by hydroxylation into metabolites that retain the biological activity of the parent compounds.

PHARMACOKINETICS of TCAsPHARMACOKINETICS of TCAs

• TCAs are strongly bound to plasma proteins.

Average t1/2:Average t1/2: 24 hours 24 hours

Up to 72 hours in Up to 72 hours in overdoseoverdose

Large T1/2 and large VD because TCA Large T1/2 and large VD because TCA extensively bound to plasma protein extensively bound to plasma protein

(90-95 %)(90-95 %)

Side Effects of TCAsSide Effects of TCAs

All tricyclics block:All tricyclics block:

- - αα1 adrenergic 1 adrenergic

- H1 histaminergic- H1 histaminergic

- M1 cholonergic receptor- M1 cholonergic receptor

- Na+ channels- Na+ channels

- - Potassium channelPotassium channel



Side effects of TCAsSide effects of TCAs

Four major toxic syndromes (A, C, S, D)Four major toxic syndromes (A, C, S, D)

A = AnticholinergicA = Anticholinergic

C = CardiovascularC = Cardiovascular

S = SeizuresS = Seizures

D = DeathD = Death

ANTICHOLINERGIC EFFECTSANTICHOLINERGIC EFFECTS

Sedation, Delirium, comaSedation, Delirium, coma TachycardiaTachycardia MydriasisMydriasis Dry mucous membranes and skinDry mucous membranes and skin Dry mouthDry mouth Decreased or absent bowel soundsDecreased or absent bowel sounds Constipation Constipation Urinary retentionUrinary retention

CARDIOVSCULAR EFFECTSCARDIOVSCULAR EFFECTS

1-1- Postural Hypotension due to venodilatation Hypotension due to venodilatation (alpha-adrenergic blocking action).

2- 2- Cardiac arrhythmias (due to increased catecholamine activity as a result of inhibition of monoamine reuptake).

3- ECG findings includes:3- ECG findings includes:

-- Sinus TachycardiaSinus Tachycardia-- Prolongation of PR, QRS, and QT intervals.Prolongation of PR, QRS, and QT intervals.-- AV blocksAV blocks-- Prolongation of QRS > 100msProlongation of QRS > 100ms

- Predictor of adverse outcome- Predictor of adverse outcome- Indication for treatment- Indication for treatment

CARDIOVSCULAR EFFECTSCARDIOVSCULAR EFFECTS

4- Inhibit neuronal catecholeamines reuptake4- Inhibit neuronal catecholeamines reuptake

5- Inhibit alpha-adrenergic receptors induces 5- Inhibit alpha-adrenergic receptors induces vasodilatationvasodilatation

6- Membrane Depressant (quinidine like) 6- Membrane Depressant (quinidine like) effects cause myocardial depression and effects cause myocardial depression and cardiac conduction disturbance due to:cardiac conduction disturbance due to:

** Sodium channel blockadeSodium channel blockade

** Potassium channel blockadePotassium channel blockade

SEIZURESSEIZURES

* The muscular hyperactivity from seizures * The muscular hyperactivity from seizures combined with decreased sweating can combined with decreased sweating can lead to severe lead to severe HYPERTHERMIAHYPERTHERMIA resulting resulting in in Rhabdomyolysis, brain damage, Rhabdomyolysis, brain damage, multisystem multisystem failure and death. failure and death.

* * Seizures occur as a result of inhibition of Seizures occur as a result of inhibition of reuptake of Norepinepherine and serotonin in reuptake of Norepinepherine and serotonin in the brain.the brain.

* * TCAs TCAs lower the seizure threshold.

DeathDeath

Sudden Death Occurs from:Sudden Death Occurs from:

1- Ventricular fibrillation1- Ventricular fibrillation

2- Status Epilepticus2- Status Epilepticus

3- Hyperthermia3- Hyperthermia

Interaction of TCA with other drugsInteraction of TCA with other drugs TCA are strongly bound to plasma proteinTCA are strongly bound to plasma protein, ,

therefore their effect can be potentiated by drugs that compete for their plasma protein binding site ( Aspirin and Phenylbutazone).

• TCAs are metabolized by liver microsomal enzymes, therefore their effect can be reduced by inducers of liver microsomal enzymes (Barbiturates), or potentiated by inhibitors of liver microsomal enzymes (Oral contraceptives, Antipsychotics, and SSRIs).

ContraindicationsContraindications

TCAs should not be used in patients with TCAs should not be used in patients with Glaucoma Glaucoma or with or with enlarged prostateenlarged prostate because because of their of their atropine-like actionatropine-like action..

TCA should not be given with MAOIsTCA should not be given with MAOIs because because TCAs (inhibitors of monoamine reuptake) can interact with MAOIs (inhibitors of monoamine degradation) leading to "hypertensive crisis".

DIAGNOSIS of TCAs OverdoseDIAGNOSIS of TCAs Overdose

1- Specific levels:1- Specific levels:

Therapeutic Plasma concentrationsTherapeutic Plasma concentrations

are are < 300 ng / ml< 300 ng / ml

Total concentrations of parent drugTotal concentrations of parent drug

plus metabolite plus metabolite (1000 ng / ml or greater)(1000 ng / ml or greater)

are associated with serious poisoning are associated with serious poisoning

2- ECG monitoring2- ECG monitoring

A- A- Ventricular Tachycardia:Ventricular Tachycardia:

B- Torsades De Point (TDP):B- Torsades De Point (TDP):

* QT prolongation* QT prolongation

* Prolonged repolarization leads to* Prolonged repolarization leads to

ventricular fiberllation and sudden death.ventricular fiberllation and sudden death.

* Occurs due to blockade of K+ channels.* Occurs due to blockade of K+ channels.

Prolongation of repolarization results in Prolongation of repolarization results in activation of an inward depolarization current activation of an inward depolarization current ( An early after depolarization( An early after depolarization). ).

“Twisting (spindle) about the Points” (node) (node)

“Spindle-node” pattern “Spindle”

“Node” (“point”)

TREATMENTTREATMENT

1- Emergency and supportive measure:1- Emergency and supportive measure:

1- Maintain an open airway and assist ventilation1- Maintain an open airway and assist ventilation2- Treat coma2- Treat coma3- Treat Seizures3- Treat Seizures4- Treat Hyperthermia4- Treat Hyperthermia5- Treat Hypotension5- Treat Hypotension6- Treat Dysrhythmia6- Treat Dysrhythmia

Note: Avoid Type Ia antiarrhythmic agents (quinidine,Note: Avoid Type Ia antiarrhythmic agents (quinidine, procainaminde, disopyramide) and Type IC (ecainide,procainaminde, disopyramide) and Type IC (ecainide, flecainide, propafenone) because these drugs aggravatesflecainide, propafenone) because these drugs aggravates cardiotoxicity as they Inhibit fast sodium channelscardiotoxicity as they Inhibit fast sodium channels

2- Medications2- Medications

1-1- Sodium Bicarbonate (1-2 mEq/kg IV) in patients Sodium Bicarbonate (1-2 mEq/kg IV) in patients with:with:

QRS > 100 msQRS > 100 msDysrhythmiasDysrhythmiasCardiac arrestCardiac arrestHypotensionHypotension

Action of Sodium bicarbonateAction of Sodium bicarbonate

1- Maintain arterial PH (7.4-7.5)1- Maintain arterial PH (7.4-7.5)

2- Reverses the membrane depressant effect by increasing2- Reverses the membrane depressant effect by increasing the extracellular Sodium concentration and by direct the extracellular Sodium concentration and by direct effecteffect

of PH on the fast sodium channelof PH on the fast sodium channel

2- Anticonvulsants:2- Anticonvulsants:

BenzodiazepinesBenzodiazepines- Lorazepam- Lorazepam- Midazolam- Midazolam- Diazepam- Diazepam

PhenobarbitalPhenobarbital- Seizures refractory to - Seizures refractory to

benzodiazepines benzodiazepines

3- Anticholinesterase: "physostigmine".

Monoamine Oxidase InhibitorsMonoamine Oxidase Inhibitors

Include:Include:

- Phenelzine- Phenelzine

- Tranylcypromine- Tranylcypromine

- Isocarboxazid- Isocarboxazid

- Moclobemide- Moclobemide

- Pargyline- Pargyline

Monoamine OxidaseMonoamine Oxidase MAO is found in nearly all tissues and is located intracellularly MAO is found in nearly all tissues and is located intracellularly

associated with mitochondria.associated with mitochondria.

Present in nerve terminals that release NA, DA or 5-HT.Present in nerve terminals that release NA, DA or 5-HT.

Located on outer surface of mitochondrial membranes.Located on outer surface of mitochondrial membranes.

Catalyses oxidative deamination of extravesicular NA, DA Catalyses oxidative deamination of extravesicular NA, DA or 5-HT.or 5-HT.

MAO regulates the free intraneuronal concentration of MAO regulates the free intraneuronal concentration of NA, 5-HTNA, 5-HT

MAO is not involved in the inactivation of released MAO is not involved in the inactivation of released transmittertransmitter

MAO EnzymeMAO Enzyme

MAO exists in tow forms coded by separate genesMAO exists in tow forms coded by separate genesMAO-A:MAO-A: has substrate preference for 5-HT and has substrate preference for 5-HT and

is is the main target for antidepressant the main target for antidepressant MAOIsMAOIs

MAO-B:MAO-B: has substrate pereference for has substrate pereference for phenylethylaminephenylethylamine

Both enzymes act on NA and dopamineBoth enzymes act on NA and dopamine

Mutation in the MAO-AMutation in the MAO-A gene causes increased brain gene causes increased brain accumulation of 5-HT and NA in the brain leading to accumulation of 5-HT and NA in the brain leading to mental retardation and aggressive behaviourmental retardation and aggressive behaviour

Monoamine Oxidase Inhibitors (MAOIs)Monoamine Oxidase Inhibitors (MAOIs)

Monoamine Oxidase Inhibitors (MAOIs)Monoamine Oxidase Inhibitors (MAOIs)

1- Irreversible and nonselective MAOIs (Classic MAOI)1- Irreversible and nonselective MAOIs (Classic MAOI)

PhenelzinePhenelzine TanylcypromineTanylcypromine IsocarboxazidIsocarboxazid pargylinepargyline

- Can not distinguish between the two isoenzymes- Can not distinguish between the two isoenzymes

- MAO-A and B enzyme activity can not be restored - MAO-A and B enzyme activity can not be restored unless new enzyme is synthesized, therefore unless new enzyme is synthesized, therefore thethe effect of MAOIs persists for a period of 2-3 weeks after stopping treatment, where a new (fresh) enzyme has to be synthesized

2-Reversible and selective inhibitors of MAO-A:2-Reversible and selective inhibitors of MAO-A:- - MoclobemideMoclobemide (antidepressant action, Short acting)(antidepressant action, Short acting)

3-3- Selective inhibitor of MAO-B:Selective inhibitor of MAO-B:- - DeprenylDeprenyl (neurodegenerative disorder) (neurodegenerative disorder)

- - SelegilineSelegiline ( (used in the treatment ofused in the treatment of

Parkinsonism)Parkinsonism)

MPTP, MAO-B and ParkinsonismMPTP, MAO-B and Parkinsonism

1-methyl-4-phenyl-tetrahydropyridine (1-methyl-4-phenyl-tetrahydropyridine (MPTPMPTP) is a protoxin that ) is a protoxin that is converted by is converted by MAO-B MAO-B to to NN-methyl-4-phenylpyridinium -methyl-4-phenylpyridinium (MPP+).(MPP+).

MPP+MPP+ is selectively taken up by cells in the substantia nigra is selectively taken up by cells in the substantia nigra through an active mechanism normally responsible for through an active mechanism normally responsible for dopamine reuptake. dopamine reuptake.

MPP+ inhibits mitochondrial complex I, thereby inhibiting MPP+ inhibits mitochondrial complex I, thereby inhibiting oxidative phosphorylation. oxidative phosphorylation. The interaction of MPP+ with The interaction of MPP+ with complex I probably leads to cell death and thus to striatal complex I probably leads to cell death and thus to striatal dopamine depletion and parkinsonismdopamine depletion and parkinsonism..

Recognition of the effects of MPTP suggested that Recognition of the effects of MPTP suggested that spontaneously occurring Parkinson's disease may result from spontaneously occurring Parkinson's disease may result from exposure to an environmental toxin that is similarly selective in exposure to an environmental toxin that is similarly selective in its target. However, no such toxin has yet been identified. its target. However, no such toxin has yet been identified.

MPTP, MAO-B and ParkinsonismMPTP, MAO-B and Parkinsonism

It also suggested a successful means of producing It also suggested a successful means of producing an experimental model of Parkinson's disease in an experimental model of Parkinson's disease in animals, especially nonhuman primates. This model animals, especially nonhuman primates. This model is assisting in the development of new is assisting in the development of new antiparkinsonism drugs.antiparkinsonism drugs.

Pretreatment of exposed animals with Pretreatment of exposed animals with MAO-B MAO-B inhibitor inhibitor such as selegilinesuch as selegiline prevents the conversion prevents the conversion of MPTP to MPP+ of MPTP to MPP+ and thus protects against the and thus protects against the occurrence of parkinsonism.occurrence of parkinsonism.

This observation has provided one reason to believe This observation has provided one reason to believe that selegiline may retard the progression of that selegiline may retard the progression of Parkinson's disease in humansParkinson's disease in humans

MAOIsMAOIs Pharmacologicals effects:Pharmacologicals effects:

MAOIs increase the cytoplasmic concentration of MAOIs increase the cytoplasmic concentration of monoamines in nerve terminalmonoamines in nerve terminal

Increases cytoplasmic pool results in spontaneous Increases cytoplasmic pool results in spontaneous leakage of monoamines and also an increased leakage of monoamines and also an increased release by indirectly acting sympathomimetic release by indirectly acting sympathomimetic amines as amphetamine and Tyramine. These amines as amphetamine and Tyramine. These amines work by displacing NA from the vesicles into amines work by displacing NA from the vesicles into the nerve terminal cytoplasm from which it may the nerve terminal cytoplasm from which it may either leak out and produce response or degraded either leak out and produce response or degraded by MAOby MAO

Side Effects of MAOIsSide Effects of MAOIs1- Hypotension:1- Hypotension: After MAO inhibition, other amines such as dopamine or After MAO inhibition, other amines such as dopamine or

octapamine are able to accumulate in peripheral sympathetic nerve terminals octapamine are able to accumulate in peripheral sympathetic nerve terminals and displace vesicular NA, thus reducing NA release and sympathetic activity and displace vesicular NA, thus reducing NA release and sympathetic activity (sympathetic block). (sympathetic block). Octapamine (Octapamine (False transmitter) Formed from tyramine in False transmitter) Formed from tyramine in the presence of MAOI. Accumulates in adrenergic synaptic vesicles thus the presence of MAOI. Accumulates in adrenergic synaptic vesicles thus sympatholytic effects, decreased BPsympatholytic effects, decreased BP

2- Antimuscarinic effects (atropine-like side-effects):2- Antimuscarinic effects (atropine-like side-effects):Dry mouthDry mouthblurred visionblurred visionUrinary retentionUrinary retention

3- CNS stimulation:3- CNS stimulation:

InsomniaInsomniaTremors Tremors excitementexcitementconvulsionsconvulsions

4- Weight gain4- Weight gain: : associated with increased appetiteassociated with increased appetite

Drug interactions of MAOIS

1- Pethidine:1- Pethidine: MAOIsMAOIs interact with the interact with the opioid receptoropioid receptor agonist (pethidine)agonist (pethidine) which may cause which may cause severe hyperpyrexia, restlessness,severe hyperpyrexia, restlessness, coma, hypotension.coma, hypotension. The mechanism The mechanism

still unclear – but it is likely that an still unclear – but it is likely that an abnormal pethidine metabolite is abnormal pethidine metabolite is produced because of inhibition of produced because of inhibition of normal demethylation pathway..normal demethylation pathway..

Drug interactions of MAOIS

2- Amphetamine and Ephedrine:2- Amphetamine and Ephedrine:

IIndirectly acting sympathomimetics can interact with MAOIs causing the liberation of accumulated monoamines in neuronal terminals leading to hypertensive crisis.

3-TCAs (inhibitors of monoamine reuptake) can interact with MAOIs (inhibitors of monoamine degradation) leading to hypertensive crisis.

Drug interactions of MAOIs

4. Levodopa: precursor of dopamine can interact with MAOIs leading to hypertensive crisis.

5. Tyramine: indirectly acting sympathomimetic amine present in many food stuffs, e.g. cheese, yogurt, yeast extracts,..) can interact with MAOIs leading to hypertensive crisis known as "cheese reaction".

• Tyramine is normally metabolized by MAO in gut and liver and so little dietary tyramine reaches systemic circulation.

• If unmetabolized, tyramine enters sympathetic nerve terminals where it displaces NA from vesicles into cytosol.

CH CH NH

HO

2 2 2

Tyramine

CH CH NH

HO

OH

22

Noradrenaline

OH

2

MAOIs interaction with tyramineMAOIs interaction with tyramine (‘cheese reaction’) (‘cheese reaction’)

• Because MAO in the nerve terminals is inhibited Because MAO in the nerve terminals is inhibited there isthere is a massive ‘non-physiological’ release of NA a massive ‘non-physiological’ release of NA from sympathetic nerve terminals which can lead to from sympathetic nerve terminals which can lead to acute hypertensive crises, severe headache and fatal acute hypertensive crises, severe headache and fatal intracranial haemorrhage.intracranial haemorrhage.

• Patients prescribed an MAOI are warned not to eat or Patients prescribed an MAOI are warned not to eat or drink certain substances (substances that contain drink certain substances (substances that contain tyramine etc.) e.g. beer, wine, cheese, marmite.tyramine etc.) e.g. beer, wine, cheese, marmite.

• At least 10 mg tyramine needs to be ingested to At least 10 mg tyramine needs to be ingested to produce this reaction.produce this reaction.

• The special The special advantage claimed for the reversible MAOI advantage claimed for the reversible MAOI is that, is that, No cheese reaction occurs with MoclobemideNo cheese reaction occurs with Moclobemide..

Selective 5-HT reuptake inhibitors (SSRIs)Selective 5-HT reuptake inhibitors (SSRIs)

- Fluoxetine (prozac)- Fluoxetine (prozac)20-80 mg/d20-80 mg/d

- Fluvoxamine (luvox)- Fluvoxamine (luvox)50-300 mg/d50-300 mg/d

- Paroxetine (paxil)- Paroxetine (paxil)20-50 mg/d20-50 mg/d

- Sertraline (zoloft)- Sertraline (zoloft) 50-200 mg/d50-200 mg/d

- Citalopram- Citalopram Initiate with 10-20 mg/dInitiate with 10-20 mg/d

Selective Seretonin Reuptake InhibitorsSelective Seretonin Reuptake Inhibitors

Selective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors

The SSRIs are currently the most widely utilized class of The SSRIs are currently the most widely utilized class of antidepressants in clinical practice.antidepressants in clinical practice.

They act within the brain to increase the amount of the They act within the brain to increase the amount of the neurotransmitter, serotonin (5-hydroxytryptamine or 5-HT), neurotransmitter, serotonin (5-hydroxytryptamine or 5-HT), in the synaptic gap by inhibiting its re-uptake.in the synaptic gap by inhibiting its re-uptake.

Instead of being discovered by accident, SSRIs were Instead of being discovered by accident, SSRIs were

specifically designed while considering the biological specifically designed while considering the biological causes of depression. causes of depression.

SSRIs are described as 'selective' because they affect only SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine to earlier antidepressants, which affect other monoamine neurotransmitters as well.neurotransmitters as well. Because of this, SSRIs lack Because of this, SSRIs lack some of the side effects of the more general drugs.some of the side effects of the more general drugs.

Side effects of SSRIs:

SSRIs are free from the side effects of TCAs (cardiac arrhythmias, antimuscarinic effects, postural hypotension) and are less dangerous in overdose, Therefore, they are the most widely used antidepressants.

Side effects include: nausea, insomnia, and sexual dysfunction.

Drug interactions of SSRIs

• SSRIs are potent inhibitors of liver microsomal enzymes. Therefore they should not be used in combination with TCAs because they can inhibit their metabolism increasing their toxicity.

• SSRIs should not be used in combination with MAOIs because of the risk of life-threatening "serotonin syndrome" (tremors, hyperthermia, cardiovascular collapse and death). Both drugs require a "washout" period of 6 weeks before the administration of the other.


SSRI drugs include many of the popular drugs on the SSRI drugs include many of the popular drugs on the market todaymarket today

They include Fluoxetine (Prozac) and Sertraline (Zoloft).They include Fluoxetine (Prozac) and Sertraline (Zoloft).

Fluoxetine Sertraline

Fluoxetine (Prozac)Fluoxetine (Prozac)

Fluoxetine, also known as Prozac, was initially Fluoxetine, also known as Prozac, was initially approved for treatment of depression in Belgium in approved for treatment of depression in Belgium in 198617, and then Eli Lilly's Prozac was approved by 198617, and then Eli Lilly's Prozac was approved by the FDA on December 27th 1987 and introduced in the FDA on December 27th 1987 and introduced in the United States at the beginning of 1988.the United States at the beginning of 1988.

Prozac was the first of a new class of drugs, called Prozac was the first of a new class of drugs, called

selective serotonin reuptake inhibitors (SSRIs), to be selective serotonin reuptake inhibitors (SSRIs), to be approved for use in the United States.approved for use in the United States.

Fluoxetine hydrochloride is an antidepressant for Fluoxetine hydrochloride is an antidepressant for oral administration. It is chemically unrelated to oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available tricyclic, tetracyclic, or other available antidepressant agents. antidepressant agents.

Fluoxetine (Prozac) cont’dFluoxetine (Prozac) cont’d

The body eliminates Fluoxetine very slowly. The body eliminates Fluoxetine very slowly.

The half-life of fluoxetine after a single dose is 2 days and after The half-life of fluoxetine after a single dose is 2 days and after multiple dosing 4 days.multiple dosing 4 days.

The liver then metabolizes The liver then metabolizes fluoxetinefluoxetine into into norfluoxetinenorfluoxetine, a , a desmethyl metabolite, which is also a serotonin reuptake desmethyl metabolite, which is also a serotonin reuptake inhibitor.inhibitor.

Norfluoxetine has an even longer half-life, i.e. 8.6 and 9.3 days Norfluoxetine has an even longer half-life, i.e. 8.6 and 9.3 days for single and repeated dosage respectively.for single and repeated dosage respectively.

Because fluoxetine's metabolism involves the P450IID6 system, Because fluoxetine's metabolism involves the P450IID6 system, concomitant therapy with drugs also metabolized by this concomitant therapy with drugs also metabolized by this enzyme system (such as the tricyclic antidepressantsenzyme system (such as the tricyclic antidepressants) ) may may lead to drug interactions. lead to drug interactions.

Sertraline (Zoloft)Sertraline (Zoloft)

Sertraline HCl is a selective serotonin Sertraline HCl is a selective serotonin reuptake inhibitor (SSRI) for oral reuptake inhibitor (SSRI) for oral administration. It is chemically unrelated to administration. It is chemically unrelated to other SSRIs, tricyclic, tetracyclic, or other other SSRIs, tricyclic, tetracyclic, or other available antidepressant agents. available antidepressant agents.

The mechanism of action of sertraline is The mechanism of action of sertraline is presumed to be linked to its inhibition of presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT).CNS neuronal uptake of serotonin (5HT).

Sertraline (Zoloft) cont’dSertraline (Zoloft) cont’d

In vitro studies have shown that In vitro studies have shown that sertraline has no sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors;receptors; antagonism of such receptors has been antagonism of such receptors has been hypothesized to be associated with various hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. other psychotropic drugs.

Sertraline does not inhibit monoamine oxidase. Sertraline does not inhibit monoamine oxidase. SertralineSertraline undergoes extensive first pass metabolism. undergoes extensive first pass metabolism.

The principal initial pathway of metabolism for sertraline The principal initial pathway of metabolism for sertraline is is N-demethylationN-demethylation. N-desmethylsertraline has a plasma . N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. terminal elimination half-life of 62 to 104 hours.

Sertraline Dosage and Side EffectsSertraline Dosage and Side Effects

Sertraline is manufactured by Pfizer as small Sertraline is manufactured by Pfizer as small green 25 mg tablets, blue 50 mg tablets, or off-green 25 mg tablets, blue 50 mg tablets, or off-yellow 100 mg tablets. It is used in dosages of yellow 100 mg tablets. It is used in dosages of between 25 mg and a maximum of 200 mg per day.between 25 mg and a maximum of 200 mg per day.

It has a number of adverse effects including It has a number of adverse effects including insomnia, asthenia, gastrointestinal complaints, insomnia, asthenia, gastrointestinal complaints, tremours, confusion, and dizziness; it can induce tremours, confusion, and dizziness; it can induce mania or hypomania in around 0.5% of patients.mania or hypomania in around 0.5% of patients.

One property of sertraline is that it appears to be One property of sertraline is that it appears to be also a minor inhibitor of dopamine reuptake. also a minor inhibitor of dopamine reuptake.


Pharmacokinetics:Pharmacokinetics:

- absorbed orally- absorbed orally

- plasma half-life: 5-24 hours, fluoxetine- plasma half-life: 5-24 hours, fluoxetine

being longer acting (24-96 hours).being longer acting (24-96 hours).

- Paroxetine and fluoxetine are not used in - Paroxetine and fluoxetine are not used in combination with TCA because they may combination with TCA because they may inhibit TCA hepatic metabolism and hence inhibit TCA hepatic metabolism and hence increase TCA toxicityincrease TCA toxicity


Advantages:Advantages:

- The Most commonly prescribed antidepressants- The Most commonly prescribed antidepressants

- - lacks cardiovascular and anticholinergic side effects comparedlacks cardiovascular and anticholinergic side effects compared to TCAto TCA

- - In contrast to MAOI, In contrast to MAOI, they do not cause ‘cheese’ reactionthey do not cause ‘cheese’ reaction

- - safer (low risk of overdose)safer (low risk of overdose)

- Acute toxicity is less than that of MAOI or TCA- Acute toxicity is less than that of MAOI or TCA


Toxic Effects:Toxic Effects: NauseaNausea InsomniaInsomnia Decreased libido and Sexual Decreased libido and Sexual

dysfunction dysfunction SEROTONIN SYNDROME:SEROTONIN SYNDROME:

in combination with MAOI, SSRIs can in combination with MAOI, SSRIs can result in result in serotonin syndromeserotonin syndrome ( (Tremors, Tremors, hyperthermia, Muscle rigidity, hyperthermia, Muscle rigidity, cardiovascular collapse)cardiovascular collapse)


Therapeutic uses:Therapeutic uses:

Depression , obsessive –compulsive Depression , obsessive –compulsive disorder, anorexia nervosa , alcoholism , disorder, anorexia nervosa , alcoholism , obesity, post –traumatic stress disorderobesity, post –traumatic stress disorder

NE Selective Reuptake Inhibitors (NRIs)

(ReboxetineTomoxetine Selective to NE uptake

May be more effective in noradrenaline deficiency syndrome(e.g., depression associated with fatigue, apathy, cognitive disturbances), or non responders to SSRIs

Also act at presynaptic α2, postsynaptic α1, α2 and βadrenergic receptors (tremor, agitation, blood pressure)

AdvantagesAdvantages lacks antagonistic activity at histamine H1, lacks antagonistic activity at histamine H1,

muscarinic & adrenergic receptors or muscarinic & adrenergic receptors or Na+ pump as with TCA

Fewer unwanted cardiovascular effects than TCA’s.Fewer unwanted cardiovascular effects than TCA’s.

Serotonin and Noradrenaline Reuptake Inhibitors Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)(SNRIs)

Serotonin norepinephrine reuptake inhibitors (SNRIs) are a Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant used in the treatment of clinical class of antidepressant used in the treatment of clinical depression and other affective disorders.depression and other affective disorders.

They act upon two neurotransmitters in the brain that are They act upon two neurotransmitters in the brain that are known to play an important part in mood, namely, serotonin known to play an important part in mood, namely, serotonin and norepinephrine. This can be contrasted with the more and norepinephrine. This can be contrasted with the more widely-used selective serotonin reuptake inhibitors (SSRIs), widely-used selective serotonin reuptake inhibitors (SSRIs), which act only on serotonin. which act only on serotonin.

SNRIs were developed more recently than SSRIs, and there are SNRIs were developed more recently than SSRIs, and there are relatively few of them. Their efficacy as well as their tolerability relatively few of them. Their efficacy as well as their tolerability appears to be somewhat better than the SSRIs, owing to theirappears to be somewhat better than the SSRIs, owing to their compound effectcompound effect. .

These new drugs, These new drugs, because of their specificity for the serotonin because of their specificity for the serotonin and norepinephrine reuptake proteins, lack most of the adverse and norepinephrine reuptake proteins, lack most of the adverse side effects of tricyclic antidepressants and monoamine side effects of tricyclic antidepressants and monoamine oxidase inhibitors.oxidase inhibitors.

Serotonin and Noradrenaline Reuptake Inhibitors Serotonin and Noradrenaline Reuptake Inhibitors

(SNRIs(SNRIs)) Venlafaxine• Combines the action of SSRI and NRI

• Selective 5HT and NE uptake blockers

• But without α1, M1 cholinergic

or H receptor blocking

properties

• Causes dual action on serotonin

And adrenergic systems, thus

Amplifying these two systems

synergistically

Serotonin and Noradrenaline Reuptake Inhibitors Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)(SNRIs)

SNRIs are currently some SNRIs are currently some

of the newest antidepressant of the newest antidepressant

drugs available on the market, drugs available on the market,

and due to this there are only and due to this there are only

a few selected drugs that havea few selected drugs that have

been approved by the FDA been approved by the FDA

for use.for use. Venlafaxine

Venlafaxine (Effexor)Venlafaxine (Effexor)

Venlafaxine hydrochloride is a prescription Venlafaxine hydrochloride is a prescription antidepressant first introduced by Wyeth in antidepressant first introduced by Wyeth in 1993, and marketed under the trade name 1993, and marketed under the trade name Effexor®. Effexor®.

It is used primarily for the treatment of It is used primarily for the treatment of depression, generalized anxiety disorder, depression, generalized anxiety disorder, and social anxiety disorder in adults. and social anxiety disorder in adults. Venlafaxine is the first and most commonly Venlafaxine is the first and most commonly used SNRI.used SNRI.

Venlafaxine (Effexor)Venlafaxine (Effexor) The mechanism of the antidepressant action of The mechanism of the antidepressant action of

venlafaxine in humans is believed to be associated venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in with its potentiation of neurotransmitter activity in the CNS. the CNS.

Venlafaxine and its active metabolite, Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV),O-desmethylvenlafaxine (ODV), are potent inhibitors are potent inhibitors of neuronal serotonin and norepinephrine reuptake of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake.and weak inhibitors of dopamine reuptake.

Venlafaxine and ODV have no significant affinity Venlafaxine and ODV have no significant affinity for for muscarinic, histaminergic, or muscarinic, histaminergic, or αα11 adrenergic adrenergic receptors receptors

Venlafaxine Dosage and Side EffectsVenlafaxine Dosage and Side Effects

Prescribed dosages are typically in the range of Prescribed dosages are typically in the range of 75mg-225mg per day, but higher dosages are 75mg-225mg per day, but higher dosages are sometimes used for the treatment of severe or sometimes used for the treatment of severe or treatment-resistant depression. Because of its treatment-resistant depression. Because of its relatively short half-life of 4 hours, Effexor should be relatively short half-life of 4 hours, Effexor should be administered in divided dosages throughout the day.administered in divided dosages throughout the day.

Side effects may include nausea, dizziness, Side effects may include nausea, dizziness, sleepiness, abnormal ejaculation, sweating, dry sleepiness, abnormal ejaculation, sweating, dry mouth, gas or stomach pain, abnormal vision, mouth, gas or stomach pain, abnormal vision, nervousness, insomnia, loss of appetite, nervousness, insomnia, loss of appetite, constipation, confusion/agitation, tremors, and constipation, confusion/agitation, tremors, and drowsiness. drowsiness.

Norepinephrine and Dopamine Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)Reuptake Inhibitor (NDRI)

These are a class of antidepressants that are These are a class of antidepressants that are not really categorized as a special group of not really categorized as a special group of antidepressants.antidepressants.

The only antidepressant in this group is The only antidepressant in this group is

BupropionBupropion, which is an antidepressant of the , which is an antidepressant of the aminoketone class, chemically unrelated to aminoketone class, chemically unrelated to tricyclics or SSRIs. It is similar in structure to the tricyclics or SSRIs. It is similar in structure to the stimulant cathinone, and to phenethylamines in stimulant cathinone, and to phenethylamines in general. general.

Bupropion (Wellbutrin)Bupropion (Wellbutrin) Bupropion was first Bupropion was first

synthesized by Burroughs synthesized by Burroughs Research in 1966, and Research in 1966, and patented by Burroughs-patented by Burroughs-Wellcome (later Glaxo-Wellcome (later Glaxo-Wellcome) in 1974. It was Wellcome) in 1974. It was approved by the FDA in 1985 approved by the FDA in 1985 and marketed under the name and marketed under the name Wellbutrin as an Wellbutrin as an antidepressant.antidepressant.

Bupropion is designated as Bupropion is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-dimethylethyl)amino]-1-propanone hydrochloride. The propanone hydrochloride. The empirical formula is empirical formula is C13H18ClNO·HCl. C13H18ClNO·HCl. Bupropion

Bupropion (Wellbutrin)Bupropion (Wellbutrin) Bupropion is a selective catecholamine Bupropion is a selective catecholamine

(norepinephrine and dopamine) reuptake inhibitor. It (norepinephrine and dopamine) reuptake inhibitor. It has only a small effect on serotonin reuptake. It does has only a small effect on serotonin reuptake. It does not inhibit MAO. not inhibit MAO.

Bupropion is metabolised in the liver. It has at least Bupropion is metabolised in the liver. It has at least three active metabolites; hydroxybupropion, three active metabolites; hydroxybupropion, threohydrobupropion and erythrohydrobupropion. threohydrobupropion and erythrohydrobupropion. These active metabolites are further metabolised to These active metabolites are further metabolised to inactive metabolites and eliminated through inactive metabolites and eliminated through excretion into the urine. excretion into the urine.

partial agonist at 5-HT type IA receptors (decrease 5HT activity ) but enhances dopaminergic and noradrenergic activity

Bupropion and its Bupropion and its MetabolitesMetabolites

Bupropion DosageBupropion Dosage

Wellbutrin pills are Wellbutrin pills are available in three available in three forms: immediate forms: immediate release, sustained release, sustained release (SR) and release (SR) and extended release extended release (XL). Generic forms of (XL). Generic forms of immediate and immediate and sustained release are sustained release are available.available.

NameName DosageDosage ColorColor

WellbutrinWellbutrin 75 mg75 mg yellow-goldyellow-gold

WellbutrinWellbutrin 100 mg100 mg redred

Wellbutrin SRWellbutrin SR 100 mg100 mg blueblue

Wellbutrin SRWellbutrin SR 150 mg150 mg purplepurple

Wellbutrin SRWellbutrin SR 200 mg200 mg pinkpink

Zyban SRZyban SR 150 mg150 mg purplepurple

Wellbutrin XLWellbutrin XL 150 mg150 mg whitewhite

Wellbutrin XLWellbutrin XL 300 mg300 mg whitewhite

Bupropion Side EffectsBupropion Side Effects

Common side effects include dry mouth, Common side effects include dry mouth, tremors, anxiety, loss of appetite, agitation, tremors, anxiety, loss of appetite, agitation, dizziness, headache, excessive sweating, dizziness, headache, excessive sweating, increased risk of seizure, and insomnia. increased risk of seizure, and insomnia. Bupropion causes less insomnia if it is taken Bupropion causes less insomnia if it is taken just before going to bed.just before going to bed.

Sexual side effects normally accompanying Sexual side effects normally accompanying SSRI's do not accompany bupropion. SSRI's do not accompany bupropion. Interestingly, patients commonly report Interestingly, patients commonly report increased libido, perhaps evidence of its increased libido, perhaps evidence of its dopaminergic properties.dopaminergic properties.

Serotonin-2A Antagonist and Reuptake Inhibitors (SARI)

TrazodoneNefazodone

Blocks 5HT uptake selectively but in a less potent manner thantricyclics

This helps reduces depression

However, they are powerful 5HT2A antagonists

But blockade of 5HT2A receptors stimulate 5HT1A receptors, which may help reduce depression

5HT2A antagonism also reduces the risk of anxiety, sedation orsexual dysfunction which is normally associated with SSRIs

Noradrenergic and specific SerotonergicAntidepressant (NaSSA)

Mirtazapine

- α2 receptor antagonist

- Increase NE and 5HT levels

- Blocks 5HT2A, 5HT3 and thusreduces side effects of anxiety,and sexual dysfunction

But by blocking 5HT2C, and H1 receptors cause sideeffects: sedation, andweight gain

Electroconvulsive TherapyElectroconvulsive Therapy Stimulation through electrodes placed on either side Stimulation through electrodes placed on either side

of the head with the patient anaesthetized, paralysed of the head with the patient anaesthetized, paralysed with a NMB drugs to avoid physical injury and with a NMB drugs to avoid physical injury and artificially ventilatedartificially ventilated

Response rates 60-80 %Response rates 60-80 % The most effective treatment The most effective treatment

for severe suicidal depressionfor severe suicidal depression DISADVANTAGESDISADVANTAGES

ConfusionConfusion

Memory loss lasting for days or weeksMemory loss lasting for days or weeks

Antimanic agents or mood stabilizers

Lithium Carbonate:

Drug of choice for bipolar Depression Decrease release of norepinephrine and

dopamine but not serotonin Increase choline uptake and acetylcholine

synthesis Decrease second messengers (interfere

with IP3 and c-AMP formation)

Proposed Mood Stabilising Mechanism Proposed Mood Stabilising Mechanism of Action of Lithium Saltsof Action of Lithium Salts

Lithium carbonate

Neurotransmitter Receptor

IP3 formation

Signalling events involving other receptors

Hormone-induced cAMP production (but not thought to be a significant mechanism in brain)

X

Effect of lithium on the IP3 and DAG second-messenger system.

The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein; EFFECTS, activation of protein kinase C, mobilization of intracellular Ca2+, etc.). Lithium, by inhibiting the recycling of inositol substrates, may cause depletion of the second-messenger source PIP2 and therefore reduce the release of IP3 and DAG.

Lithium Carbonate

Lithium is clinically effective at Lithium is clinically effective at plasma plasma concentration of 0.5-1 mM.concentration of 0.5-1 mM.

Above 1 mm, it produces a variety of toxic effects, Above 1 mm, it produces a variety of toxic effects, therefore, monitoring of plasma concentration is therefore, monitoring of plasma concentration is essentialessential

After the drug is started, 7-10 day must After the drug is started, 7-10 day must be elapsed before the antimanic effect be elapsed before the antimanic effect is reached.is reached.

Lithium causes Lithium causes depletion of membrane depletion of membrane phosphatidylinositol and accumulation phosphatidylinositol and accumulation of intracellular inositol phosphateof intracellular inositol phosphate..

Hormone-mediated cAMP production is Hormone-mediated cAMP production is reducedreduced

Lithium Carbonate

Rely on their ability to stabilize mood.

Used prophylactically.

Narrow therapeutic index (produce kidney damage at doses very close to therapeutic doses).

May act by inhibiting phosphoinositide signal transduction thereby reducing neurotransmission.

Pharmacology of Lithium Salts

no effect in normal person stabilizes mood in affective disorder low therapeutic index toxicity: correlated with plasma

concentration; fine tremors, ataxia, confusion, delirium, convulsions, cardiac arrhythmias

treatment should be under normal Na+ intake

and normal cardiac and renal function

Therapeutic uses

Bipolar disorder

Mania

Major depression

Neutropenia (chemotherapy -& zidovudine–induced neutropenia)

•SIADH (syndrore of inappropriate secretion of ADH)

Lithium Carbonate Adverse effects Anorexia , diarrhoea , hypothyroidism ,

seizures (Convulsion and death if plasma concentration reaches 3-5 Mm).

leukocytosis , nephrotic syndrome and polyuria , impotence.

A toxic drug ; adverse reactions are dose-and concentration-dependent .

Renal Adverse EffectsRenal Adverse Effects

Polydipsia and polyuriaPolydipsia and polyuria are frequent but reversible are frequent but reversible concomitants of lithium treatment, occurring at concomitants of lithium treatment, occurring at therapeutic serum concentrations.therapeutic serum concentrations.

The principal physiologic lesion involved is loss of The principal physiologic lesion involved is loss of the ability of the collecting tubule to conserve water the ability of the collecting tubule to conserve water under the influence of antidiuretic hormone, under the influence of antidiuretic hormone, resulting in excessive free water clearance.resulting in excessive free water clearance.

Patients receiving lithium should avoid dehydration Patients receiving lithium should avoid dehydration and the associated increased concentration of and the associated increased concentration of lithium in urine. Periodic tests of renal concentrating lithium in urine. Periodic tests of renal concentrating ability should be performed to detect changesability should be performed to detect changes..

EdemaEdema

EdemaEdema is a frequent adverse effect of is a frequent adverse effect of lithium treatment and may be related to lithium treatment and may be related to some effect of lithium on sodium some effect of lithium on sodium retention. Although weight gain may be retention. Although weight gain may be expected in patients who become expected in patients who become edematous, water retention does not edematous, water retention does not account for the weight gain observed in account for the weight gain observed in up to 30% of patients taking lithium.up to 30% of patients taking lithium.

Cardiac Adverse EffectsCardiac Adverse Effects

The bradycardia-tachycardia The bradycardia-tachycardia

("sick sinus") syndrome("sick sinus") syndrome is a definite is a definite contraindication to the use of lithium contraindication to the use of lithium because the ion further depresses the because the ion further depresses the sinus node. T wave flattening is often sinus node. T wave flattening is often observed on the ECG but is of observed on the ECG but is of questionable significance questionable significance

Use During PregnancyUse During Pregnancy

Lithium is transferred to nursing infants through Lithium is transferred to nursing infants through breast milk, in which it has a concentration about breast milk, in which it has a concentration about one-third to one-half that of serum. Lithium toxicity one-third to one-half that of serum. Lithium toxicity in newborns is manifested by lethargy, cyanosis, in newborns is manifested by lethargy, cyanosis, poor suck and Moro reflexes, and perhaps poor suck and Moro reflexes, and perhaps hepatomegaly.hepatomegaly.

The issue of dysmorphogenesis is not settled. An The issue of dysmorphogenesis is not settled. An earlier report suggested an increase in the frequency earlier report suggested an increase in the frequency of cardiac anomalies, especially Ebstein's anomaly, of cardiac anomalies, especially Ebstein's anomaly, in lithium babies, but the most recent data suggest in lithium babies, but the most recent data suggest that lithium carries a relatively low risk of that lithium carries a relatively low risk of teratogenic effects.teratogenic effects.

Drug InteractionsDrug Interactions

Renal clearance of lithium is reduced about 25% by thiazide Renal clearance of lithium is reduced about 25% by thiazide diuretics (diuretics (hydrochlorothiazide, chlorothiazidehydrochlorothiazide, chlorothiazide) and doses may ) and doses may need to be reduced by a similar amount. need to be reduced by a similar amount.

A similar reduction in lithium clearance has been noted with A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins (Iblock synthesis of prostaglandins (Ibuprofen, Indomethacin). buprofen, Indomethacin). This interaction has not been reported for either aspirin or This interaction has not been reported for either aspirin or acetaminophen. acetaminophen.

All neuroleptics tested to date, with the possible exception of All neuroleptics tested to date, with the possible exception of clozapine and the newer antipsychotics, may produce more clozapine and the newer antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium.severe extrapyramidal syndromes when combined with lithium.

Other Antimanic Agents

1- Valproic acid:facilitates GABAergic transmission; preferred over lithium for initial therapy but lithium is still preferred for maintenance treatment

2- Carbamazepine:reduces release of neurotransmitters

3- Gabapentin:inhibits GABA uptake

4- Lamotrigine4- Lamotrigine

Valproic acid

valproic acid has been effective in some patients who have valproic acid has been effective in some patients who have failed to respond to lithiumfailed to respond to lithium

The starting dose is 750 mg/d, increasing rapidly toThe starting dose is 750 mg/d, increasing rapidly to

the 1500–2000 mg range with a recommended maximum dose the 1500–2000 mg range with a recommended maximum dose of 60 mg/kg/d.of 60 mg/kg/d.

Combinations of valproic acid with other psychotropic Combinations of valproic acid with other psychotropic medications likely to be used in the management of either medications likely to be used in the management of either phase of bipolar illness are generally well tolerated.phase of bipolar illness are generally well tolerated.

Many clinicians argue for combining valproic acid and lithium Many clinicians argue for combining valproic acid and lithium

in patients who do not fully respond to either agent alone.in patients who do not fully respond to either agent alone.

LamotrigineLamotrigine Lamotrigine is an anticonvulsant Lamotrigine is an anticonvulsant

drug used in the treatment ofdrug used in the treatment ofepilepsy and bipolar disorder. epilepsy and bipolar disorder.

. Lamotrigine also acts as. Lamotrigine also acts as a mood stabilizer. It is thea mood stabilizer. It is the first medication since lithiumfirst medication since lithium to be granted approval by the to be granted approval by the U.S. Food and Drug Administration U.S. Food and Drug Administration (FDA) for the maintenance treatment(FDA) for the maintenance treatment

of bipolar type I.)of bipolar type I.)

lamotrigine is most effective in the lamotrigine is most effective in the treatment and prophylaxis of bipolar treatment and prophylaxis of bipolar depressiondepression

Mechanism of actionMechanism of action

One proposed mechanism of action for One proposed mechanism of action for lamotrigine involves an effect on sodium lamotrigine involves an effect on sodium channels, although this remains to be channels, although this remains to be established in humans. established in humans. In vitroIn vitro pharmacological studies suggest that pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal channels, thereby stabilizing neuronal membranes and consequently modulating membranes and consequently modulating presynaptic transmitter release of excitatory presynaptic transmitter release of excitatory amino acids (for example glutamate and amino acids (for example glutamate and aspartate).aspartate).

Pharmacokinetic dataPharmacokinetic data

BioavailabilityBioavailability 98%98% Protein bindingProtein binding 55%55% MetabolismMetabolism HepaticHepatic Half lifeHalf life 24-34 24-34

hours Excretionhours Excretion RenalRenal

Side effectsSide effects Lamotrigine prescribing information has a black box Lamotrigine prescribing information has a black box

warning about life threatening skin reactions, warning about life threatening skin reactions, including Stevens-Johnson Syndrome and Toxic including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. The manufacturer states that Epidermal Necrolysis. The manufacturer states that nearly all cases appear in the first 2 to 8 weeks of nearly all cases appear in the first 2 to 8 weeks of therapy and if medication is suddenly stopped then therapy and if medication is suddenly stopped then resumed at the normal dosage. Patients should seek resumed at the normal dosage. Patients should seek medical attention for any unexpected skin rash as its medical attention for any unexpected skin rash as its presence is an indication of a possible serious or presence is an indication of a possible serious or even deadly side effect of the drug. even deadly side effect of the drug.

Lamotrigine binds to melanin-containing tissues Lamotrigine binds to melanin-containing tissues such as the iris of the eye. The long-term such as the iris of the eye. The long-term consequences of this are unknown.consequences of this are unknown.

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