Monoamine Monoamine Oxidase InhibitorsOxidase Inhibitors

Monoamine oxidase inhibitors

MMonoamine onoamine OOxidase xidase IInhibitornhibitorss ( (MAOIsMAOIs) ) are a class of powerful antidepressant are a class of powerful antidepressant drugs. They are particularly effective in drugs. They are particularly effective in treating treating atypical depression, panic atypical depression, panic disorders, social phobiadisorders, social phobia

Due to potentially lethal dietary and drug Due to potentially lethal dietary and drug interactions, MAOIs had been reserved interactions, MAOIs had been reserved as a as a last line of Rxlast line of Rx, , used only when other used only when other classes of antidepressant drugs (e.g. SSRIs classes of antidepressant drugs (e.g. SSRIs and TCAs) have failedand TCAs) have failed

What is Monoamine What is Monoamine Oxidase?Oxidase?

MAO is a MAO is a mitochondrial enzyme mitochondrial enzyme found in most found in most tissues; NS, liver, gut (tissues; NS, liver, gut (presynaptic nerves). presynaptic nerves).

The enzyme is responsible for the degradation The enzyme is responsible for the degradation of monoamine neurotransmittersof monoamine neurotransmitters

There are two forms of monoamine There are two forms of monoamine oxidase; MAO-A and MAO-Boxidase; MAO-A and MAO-B

MAO-A is responsible for NE, 5-HT & tyramine metabolism

MAO-B is more selective for dopamine metabolism

Mechanism of action

MAOIsMAOIs act by inhibiting the act by inhibiting the activity of activity of MAOMAO thus preventing thus preventing the breakdown of monoamine the breakdown of monoamine neurotransmitters and thereby neurotransmitters and thereby increasing their availability in increasing their availability in

the synaptic cleft the synaptic cleft

Site of Action of MAOIsSite of Action of MAOIs

The early MAOIs inhibited MAO The early MAOIs inhibited MAO irreversibly.irreversibly. i.e they permanently i.e they permanently deactivate it, and the enzyme cannot deactivate it, and the enzyme cannot function until it has been replaced by the function until it has been replaced by the body, which can take about body, which can take about two weeks. two weeks.

A few newer MAOIs, A few newer MAOIs, moclobemidemoclobemide, are , are reversiblereversible, they are able to detach from , they are able to detach from the enzyme. the enzyme.

Classification of MAOIs

According to According to Reversibility, Reversibility, MAOIs can be classified MAOIs can be classified intointo: :

11-Irreversible agents-Irreversible agents;;Tranylcypromine, Tranylcypromine, phenelzine phenelzine irreversiblyirreversibly combine with the enzyme & have a combine with the enzyme & have a prolonged action prolonged action

2-2- Reversible agents Reversible agents;;- - MoclobemideMoclobemide..

Classification of MAOIs

According to selectivity, MAOIs According to selectivity, MAOIs can be classified into: can be classified into:

11-Non selective agents-Non selective agents;;Phenelzine,TranylcyprominePhenelzine,TranylcypromineThey inhibit MAO A, MAO B They inhibit MAO A, MAO B 2-2- Selective agents Selective agents;;--MoclobemideMoclobemide, (MAO-A)I, (MAO-A)I-Selegiline, (MAO-B)I-Selegiline, (MAO-B)I..

Many foods containing Many foods containing tyraminetyramine is normally is normally degraded in the gut by degraded in the gut by MAO-AMAO-A

Since the enzyme is inhibited by MAOIs, Since the enzyme is inhibited by MAOIs, tyraminetyramine from ingested food is absorbed, and then taken up from ingested food is absorbed, and then taken up into adrenergic neurons. into adrenergic neurons.

It is converted into It is converted into octopamineoctopamine - a false - a false transmitter which causes massive release of transmitter which causes massive release of NENE and may result and may result in hypertensive crisis in hypertensive crisis

-. -.

People taking People taking MAOI’s should MAOI’s should avoid foods rich avoid foods rich in in tyraminetyramine

e.g.e.g.aged wine aged wine , aged cheese, , aged cheese, liver, sausages, liver, sausages, fish fish

Some meat Some meat and yeast and yeast extractsextracts

Drug Interactions

1-The use of 1-The use of MAO inhibitors MAO inhibitors with with TCAs TCAs causes elevated causes elevated levels of NE and hypertensive levels of NE and hypertensive crisiscrisis

2-Concurrent use of a 2-Concurrent use of a MAOIMAOI and and fluoxetinefluoxetine may lead to the may lead to the serotonin syndromeserotonin syndrome

Drug Interactions3-3-Local anaesthetics Local anaesthetics or or cold medications contain cold medications contain

(pseudoephedrine, ephedrine) (pseudoephedrine, ephedrine) have synergistic effects have synergistic effects with the increased levels of catecholamines caused by MAOIs with the increased levels of catecholamines caused by MAOIs

5-5-MAOIsMAOIs with with pethidinepethidine may lead to abnormal syndrome may lead to abnormal syndrome characterized by characterized by hyperpyrexia, irritability, hypotension hyperpyrexia, irritability, hypotension and coma and coma due to an abnormal pethidine metabolite due to an abnormal pethidine metabolite resulting from the resulting from the inhibition of the normal demethylation inhibition of the normal demethylation pathway of pethidine by MAOIs pathway of pethidine by MAOIs

Current use of MAOIs

They are not the first-line drugs because They are not the first-line drugs because of the great drug interaction risks & the of the great drug interaction risks & the complicated dietary restrictions complicated dietary restrictions requiredrequired

The reversible selective MAO-A inhibitor The reversible selective MAO-A inhibitor moclobemide & moclobemide & the selective MAO-B the selective MAO-B inhibitor inhibitor selegiline selegiline have a greater safety have a greater safety margin margin

Newer MAOIs are used for the treatment Newer MAOIs are used for the treatment of of atypical depression ( + severe atypical depression ( + severe anxiety or panic attacks, marked anxiety or panic attacks, marked obesity) and obesity) and depression resistant to depression resistant to therapytherapy

Selegiline Patch (Emsam™)

Selective MAO-B InhibitorSelective MAO-B Inhibitor BioavailabilityBioavailability

Orally: Orally: 4%4%

Transdermally: Transdermally: 74%74% Avoid first pass GI exposureAvoid first pass GI exposure Much less inhibition of gut & liver Much less inhibition of gut & liver

MAO-AMAO-A

Mixed - Action & Atypical

Antidepressants

Mixed-Action Antidepressants

Selective serotonin- norepinephrine Selective serotonin- norepinephrine reuptake inhibitors ( reuptake inhibitors ( SNRIsSNRIs))

Norepinephrine reuptake inhibitors Norepinephrine reuptake inhibitors ((NRIsNRIs))

Norepinephrine-dopamine reuptake Norepinephrine-dopamine reuptake inhibitors (inhibitors (NDRIsNDRIs))

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs are a newer form of anti-SNRIs are a newer form of anti-depressants that work on both 5-HT (SSRI-depressants that work on both 5-HT (SSRI-plus)plus) and weak NE reuptake blockade and weak NE reuptake blockade

They have similar side effects to the SSRIs They have similar side effects to the SSRIs exceptexcept increased risk of hypertension increased risk of hypertension

Examples : Examples : Venlafaxine Venlafaxine

Venlafaxine

Potent inhibitor of Potent inhibitor of serotonin, NE serotonin, NE reuptake reuptake transporter transporter (SNRIs)(SNRIs)

Unlike, TCAs, has little Unlike, TCAs, has little activity at adrenergic, activity at adrenergic, histaminic and muscarinic histaminic and muscarinic receptors receptors (fewer side (fewer side effects than TCAs)effects than TCAs)

Reboxetine

NaNa reuptake reuptake inhibitor inhibitor

[ NARIs ][ NARIs ]

No affinity for No affinity for 5HT, DA, H, 5HT, DA, H, muscarinic muscarinic receptors receptors

Reboxetine

Has Has a positive effect a positive effect on the on the concentration and motivation in concentration and motivation in particular particular

Safe to combine with SSRIsSafe to combine with SSRIs Minimal side effects only related Minimal side effects only related

to activation of adrenergic to activation of adrenergic system as system as tremor, tachycardiatremor, tachycardia

Mirtazapine

Belongs to a newer class of antidepressants

acts by blocking presynaptic central alpha-2 adrenergic receptors leading to increased release of NE and serotonin

+ blocking serotonin receptors (5HT3 , 5HT2 receptors)------- > lower incidence of adverse effects such as anxiety, insomnia, and nausea 

has only minimal activity at dopaminergic and muscarinic receptors.

Mirtazapine

Does not cause Does not cause anti-muscarinic side anti-muscarinic side effects , less sexual dysfunctioneffects , less sexual dysfunction

Side effects Side effects include include sedation sedation (antihistaminic effect) and (antihistaminic effect) and weight weight gain gain

Mirtazapine is preferred in cancer patients

because: Improves appetiteImproves appetite nausea nausea & vomiting ( 5-HT& vomiting ( 5-HT33 blocking) blocking) body weightbody weight Sedation (antihistaminic)Sedation (antihistaminic) Less sexual dysfunction (5-HTLess sexual dysfunction (5-HT2 2 blocking)blocking) Has no anti-muscarinic effectHas no anti-muscarinic effect

Norepinephrine-dopamine reuptake inhibitors (NDRIs)

Bupropion (Wellbutrin ) is a Bupropion (Wellbutrin ) is a unique drug that has been unique drug that has been

shown to possess significant shown to possess significant potency potency as as NE and dopamine NE and dopamine reuptake inhibitor in the brain reuptake inhibitor in the brain with no direct action on the with no direct action on the

serotonin systemserotonin system

Therapeutic uses:Therapeutic uses: 1- Treatment of 1- Treatment of major depressionmajor depression and and bipolar depressionbipolar depression 2-Can be used in 2-Can be used in smoking smoking cessation cessation as it reduces the severity of nicotine as it reduces the severity of nicotine craving & withdrawal symptomscraving & withdrawal symptomsAdvantages:Advantages:No sexual dysfunctionNo sexual dysfunctionNo wNo weight gain (as no serotonin eight gain (as no serotonin effect)effect) No orthostatic hypotensionNo orthostatic hypotension

Side effects:Side effects: ppt seizures :it ppt seizures :it threshold of neuronal firingthreshold of neuronal firing