Monamine Oxidase InhibitorsAbigail BrewerAlex PogzebaShannon Marrs

Why MAOI’s?They have significant presence in plant

and animal life as well as traditional plant medicine

They have had a significant affect on changing treatment of psychological disorders

The sheer variety of MAOI’s in the world today

They are still used as a last resort for treatment of depression, thus, new MAOI’s are being developed

The role of Monoamine oxidase Flavin-adenosine-dinucleotide-

converts biogenic amines to aldehydes

Primary substrates in the brain are dopamine, serotonin, epinepherine, norepinepherine, and β-phenylethylamine◦ Tyramine, the precursor of dopamine is

also catabolized by MAO Two different forms: MAO-A and

MAO-B Both forms of MAO are located on

the outer membrane of the mitochondria

Widely distributed in all mammalian cell types except erythrocytes

Main function ◦ CNS- metabolism of amines and

regulation of neurotransmitter levels as well as intracellular amine stores

◦ In the GI- protective function◦ BBB-protective function

http:www.neurosoup.com/maoi.htm//

MAO-B Preferred enzyme of β-

phenylethylamine sustrate Also metabolizes tyramine,

octopamine, tryptamine and dopamine◦ Dopamine in the brain shows

a higher affinity for MAO-B Greatest abundance in

brain tissue In the CNS localized in 5-

HT cell groups, glial astrocytes, and parts of the hypothalamus

MAO-B inhibitors are being researched for treatment of Parkinson's disease

MAO-A Prefers to metabolize,

serotonin, norepinepherine Will also metabolize

tyramine, tryptamine, octoamine, and dopamine

Found in higher concentrations in the placenta, liver and intestine

Within CNS localized in cell bodies and dendrites of catecholamine cell groups◦ Mainly in the substantia

nigra, locus coeruleus, nucleus subcoeruleus, and parts of the hypothalamus

Some HistoryMAOI’s are the oldest class of

antidepressant and are still used as a last resort for patients showing signs of atypical depression

MAOI’s were first introduced in the 1950’s◦They unfortunately require dietary

restrictions and have many adverse reactions when taken with other medications

◦They take less time to work then SSRI’s

Examples of MAOI’s 1st generation Pharmaceutical-non selective

irreversible MAOI’s (most derived from hydrazine) ◦ Examples are iproniazid, tranylcypromine, phenelzine

2nd generation pharmaceutical-selectively inhibits MAO-A or MAO-B; usually reversible◦ Moclobemide, Lazabemide, Rasgiline (used in treating

Parkinsons) Plant based compounds-

◦ Harmala alkaloids, coumarins and curcumin. Liquorice, Yerba Mate, Ginkgo Balboa all contain compounds exhibiting MAOI effects. It is important to note that some of the naturally occurring MAOI

do not exist in a high enough concentration to show an observable effect when consumed by humans.

Antiparasitic-◦ Amitraz

Current uses of MAOIs: DepressionDepression is thought to be caused by

a chemical imbalance in the brainMonoamine neurotransmitters are

involved in regulating everything from body temperature to mood◦Particularly related to mood are dopamine,

serotonin, and nor adrenalineMAOI’s work by inhibiting the enzyme

that breaks down monoamines thereby increasing the levels of monoamines in the brain

Tranylcypromine Originally developed in 1948 as an analogue for

amphetamine; action as an MAOI not discovered until 1959◦ At this point all other MAOI’s were hydrazine derivatives ◦ Because Tranylcypromine was not a hydrazine derivative

clinicians originally thought it might avoid some of the complications seen in association with other MAOI’s

From the phenethylamine and amphetamine class Used as a last resort to treat depression and anxiety Non-selective and irreversible inhibitor of

Monoamine oxidase Marketed as Parnate 2 separate enantiomers: Use TCP (+) Age influences the effect

Tranylcypromine: Clinical useDepression

◦Especially treatment resistant depressionAnxietyBorderline personality disorder

◦One of the few drugs that shows an effect in BPD

Dosing-10mg pills◦15 mg minimum

Increase by 5mg/dose at 1-3 weeks to optimum response

◦No more then 60 mg/day

Tranylcypromine: Mechanism of ActionMetabolized by P450 CYP2C19Inhibition of Monoamine oxidase is not time

dependentCompetitive inhibitor of Monoamine oxidaseBinding affinity of MAO is higher for

tranylcypromine then the usual substratesCauses a conformational change in MAO in

the Gln206 and a “closed confirmation of the side chain Ile199 causing the formation of a hydrophobic sandwich with the Ile316

◦ causes a higher binding affinity of monoamine oxidase for other drugs

Tranylcypromine circulatory effectsCorrelation between mean plasma

concentrations and mean orthostatic drop in systolic blood pressure and a rise in pulse rate

Dose significantly correlated with elevated blood pressure◦Hypertensive response is mediated by

norepinepherine◦Orthostatic hypotensive effect mediated by

a direct interaction between tranylcypromine and α-adrenegic receptors

Enzymatic activity of TranylcypromineIncrease in activity of aromatic

amino acid decarboxylase enzyme

Effects uptake and release of catecholamines and 5-hydroxytrytamine in the brain

Active Metabolites of TranylcypromineHippuric acidN-acetyl-tranylcypromine

◦Nonspecific inhibitor of both MAO-A and MAO-B but weaker then the parent compound

N-acetyl-4-hydroxy-tranylcypromine

Chronic administration Presynaptic changes include down-regulation of P-

adrenoreceptors after chronic administration of Tranylcypromine

Chronic administration of Tranylcypromine causes a decrease in the density of 3H-tryptamine binding sites

Down Regulation of 5-HT2 receptors Increases the efficacy of seroternergic neurons

through down-regulation of somatodendritic autoreceptor

Down regulates both D1 and D2 receptors in striatum Low dose is enough to down regulate p-adrenergic

and tryptamine receptors High doses decrease 5-HT2 receptors in the cortex Inhibits oxidative microsomal reactions through

interaction with cytochrome p-450

Tranylcypromine toxicityAnxietyMuscle tremorsTachycardiaHypertension or

hypotensionHyperthermiaWorst case scenario

◦ Hypertensive crises◦ Serotonin syndrome◦ Myoclonus◦ Hyperprexia◦ Psychosis◦ Delirium

Drug interactions often cause a lowering of LD50 and ED50 for other prescription/ nonprescription drugs

High rate of drug interactions

Limited diet: Patient should not eat tyramine containing foods, should not take with alcohol

Tranylcypromine abusePatient may experience unprecedented

confidence, restlessness and cheerfulnessPatient will experience a loss of REM sleep as

well as high muscle tension during sleepWhen the patient runs out you will experience

dreaming by day as well as immediate onset of REM sleep in which you have nightmares

The patients nightmares will last all night longAt high dosages tryptamine excretion increases

but 5-hydroxytryptophan does not, associated with serotonin receptors

Blood levels of 5-hydroxytryptophan fall because of a possible interference with uptake in platelets

MoclobemideReversible inhibitor of MAO-AIt is derived from benzamideUsed to treat anxiety and

depression

Metabolism of MoclobemideOral administration results in 98% absorption

from the GI. High first pass effect reducing bioavailability to

55% after single dosesMultiple doses allow bioavailability to build up

to 90%Extensive tissue distributionExtensively metabolized with 95% of dose

being excreted in the urineMetabolites are not pharmacologically active50% binds to plasma proteins; mainly albuminFood reduces the rate of absorption but not

extent of absorption

Mechanism of action of RIMA’s

Moclobemide◦ Inhibitor and

substrate of P450-2C19 and P450 2C9

◦ Inhibitor, substrate and inducer of P-450 2D6

Moclobemide dosing 150 mg and 300 mg tablets Usual adult dosage less then 450 mg/kg however up to 600

mg/kg tolerated Up to 200mg pharmacokinetics were linear From 200-400 mg/kg pharmacokinetics are non-linear 400-1200 mg/kg Maximum plasma concentrations increase

in a non dose proportional manner Higher doses cause an increase in the elimination half life Steady state concentrations range between 114 ng/ml to

517 ng/ml In patients with hepatic impairment there is a three fold

increase in peak plasma concentrations Elderly patients show a higher area under the curve then

younger patients Administering Moclobemide after ingestion of tyramine

containing foods reduces potentiation of tyramine

Moclobemide Toxicity Hypertension Drowsiness Dizziness Confusion Tremors Headache Agitation Muscle rigidity Seizures Mouse LD50-730

mg/kg Rat LD50-1300 mg/kg

Dietary restrictions:◦ Administering

Moclobemide after ingestion of tyramine containing foods reduces potentiation of tyramine

◦ Limit intake of tyramine containing foods, alcohol

High rate of drug interactions although less than first generation MAOI’s

Moclobemide OverdoseNausea DrowsinessMild disorientationSlurred speech Amnesia Reduced reflexesNo organ toxicity

Moclobemide Vs. TranylcypromineSmall quantities

are excreted in human milk

Less drug interactions and dietary restrictions

Reversible and specific

No active metabolites

Irreversible non-specific

No measurable quantities are excreted in human milk

Many dietary restrictions and drug interactions

Active metabolites are less active than parent compound

The Harmala Alkaloids Harmine Harmaline d-tetrahydroharmine Harmalol Harman Family of chemicals that fit under a class of

compounds known as the β-carbolines. The Harmala alkaloids are reversable inhibitors of MAO-A (RIMA).

Some Harmala alkaloids fluoresce under UV light

Plants containing Harmala Alkaloids

Peganum harmala (Syrian rue)◦Ranges from Eastern mediterranean to India◦Found in US- mostly western states (invasive)

Banisteriopsis caapi (ayahuasca vine)◦Jungles of South America to jungles of Mesoamerica

Nicotina spp. (tobacco) ◦Indigenous to North and South America and Australia

Traditional uses of Syrian rue Traditionally used gynecologically to reduce

birthing pain and ease the birthing process Aphrodisiac Asthma remedy Menstrual difficulties Infertility Seeds used to fumigate wounds as an antiseptic Abortifacient Used to treat skin disorders Stomach ailments Heart problems Sciatica Can be used as a tranquilizer

Traditional uses for Banisteriopsis spp. Banisteriopsis caapi is used by the indigenous people of

the amazon in South America to brew the beverage known as ayahuasca which is used irreligious and healing ceremonies. Banisteriopsis caapi is used to potentiate the effects of other plants added to the brew specifically plants containing an entheogenic tryptamine DMT. Ayahuasca is then used by healers to treat a variety of ailments such as

Banisteriopsis muricata and B. inebrians are examples of others Banisteriopsis species which contain harmala alkaloids and have a history of use in ayahuasca or ayahuasca-like preparations throughout the indigenous people of South America. It has also been proposed that B. muricata was possibly used by the Maya people of Mexico and Guatemala to brew a form of ayahuasca.

B. inebrians is used by indigenous people of South America to poison and catch fish.

Modern Medical uses for Harmala alkaloids Investigation into the use of harmala alkaloids for

treatment of Parkinson's Disease was preformed in the 1920s. An extract from B. caapi was shown to help alleviate the symptoms of Parkinsonism, however the results if this study were forgotten due to some speculations about the identity of the active components of the caapi extract. In 2001 Marcos Serrano-Duenas, Fernando Cardozo-Pelaez, and Juan R. Sanchez-Ramos conducted a study in Equador which showed that Banisteriopsis caapi extract improved motor function in individuals suffering from Parkinson's Disease.

Potential use of ayahuasca to treat depression, addiction, and stress related to terminal illness are subjects currently being investigated.

Metabolism of harmala alkaloids

It has been found that CYP450 catalyze O-demethylation of harmine and harmaline, where CYP2D6 and CYP1A1 have been identified as the major isoenzymes involved in this process.

Harmol glucuronide and harmol sulfate have been found to be the main metabolites found in urine after I.V. administration of harmine and harmaline in humans and rats.

Little to no investigation of many of the other harmala alkaloids has been preformed.

Toxicity of Harmala alkaloids Adverse effects of harmala alkaloids can include: Paresthesias Numbness physical discomfort Nausea Intense vomiting Dizziness Bradycardia Trouble focusing the eyes Coldness in the extremities Hypotension An aqueous extract made from syrian rue seed

displayed a LD50 of 2g/kg when administered to rats.

Amitraz: insecticideMAOIAlso inhibits prostaglandins, interacts with octopamine receptors in CNSCauses over excitation, paralysis, and death in insectsNot very effect against mammals, used in dog flea/mite infestationRapidly bio-transformed into six metabolites in humans

Amitraz LD50’s

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