Transcript Monamine Oxidase Inhibitors

Monamine Oxidase Inhibitors
Abigail Brewer
Alex Pogzeba
Shannon 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
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The role of Monoamine oxidase
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Flavin-adenosine-dinucleotide-converts
biogenic amines to aldehydes
Primary substrates in the brain are
dopamine, serotonin, epinepherine,
norepinepherine, and βphenylethylamine
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Tyramine, the precursor of dopamine is
also catabolized by MAO
Two different forms: MAO-A and MAOB
Both forms of MAO are located on the
outer membrane of the mitochondria
Widely distributed in all mammalian cell
types except erythrocytes
Main function
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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
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Preferred enzyme of βphenylethylamine sustrate
Also metabolizes tyramine,
octopamine, tryptamine and
dopamine
◦ Dopamine in the brain shows a
higher affinity for MAO-B
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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
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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 History
MAOI’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
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◦ 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
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1st generation Pharmaceutical-non selective irreversible
MAOI’s (most derived from hydrazine)
◦ Examples are iproniazid, tranylcypromine, phenelzine
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2nd generation pharmaceutical-selectively inhibits MAO-A or
MAO-B; usually reversible
◦ Moclobemide, Lazabemide, Rasgiline (used in treating
Parkinsons)
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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.
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Antiparasitic◦ Amitraz
Current uses of MAOIs:
Depression
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Depression is thought to be caused by a
chemical imbalance in the brain
Monoamine neurotransmitters are involved
in regulating everything from body
temperature to mood
◦ Particularly related to mood are dopamine,
serotonin, and nor adrenaline
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MAOI’s work by inhibiting the enzyme that
breaks down monoamines thereby
increasing the levels of monoamines in the
brain
Tranylcypromine
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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
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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 use
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Depression
◦ Especially treatment resistant depression
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Anxiety
Borderline personality disorder
◦ One of the few drugs that shows an effect in BPD
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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
Action
Metabolized by P450 CYP2C19
Inhibition of Monoamine oxidase is not time
dependent
 Competitive inhibitor of Monoamine oxidase
 Binding affinity of MAO is higher for
tranylcypromine then the usual substrates
 Causes 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
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◦ causes a higher binding affinity of monoamine
oxidase for other drugs
Tranylcypromine circulatory effects
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Correlation 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
Tranylcypromine
Increase in activity of aromatic amino acid
decarboxylase enzyme
 Effects uptake and release of
catecholamines and 5-hydroxytrytamine
in the brain
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Active Metabolites of
Tranylcypromine
Hippuric acid
 N-acetyl-tranylcypromine
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◦ Nonspecific inhibitor of both MAO-A and
MAO-B but weaker then the parent
compound
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N-acetyl-4-hydroxy-tranylcypromine
Chronic administration
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Presynaptic changes include down-regulation of Padrenoreceptors 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 toxicity
Anxiety
 Muscle tremors
 Tachycardia
 Hypertension or
hypotension
 Hyperthermia
 Worst case scenario
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Hypertensive crises
Serotonin syndrome
Myoclonus
Hyperprexia
Psychosis
Delirium
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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 abuse
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Patient may experience unprecedented confidence,
restlessness and cheerfulness
Patient will experience a loss of REM sleep as well as
high muscle tension during sleep
When 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 long
At 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
Moclobemide
Reversible inhibitor of MAO-A
 It is derived from benzamide
 Used to treat anxiety and depression
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Metabolism of Moclobemide
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Oral administration results in 98% absorption from
the GI.
High first pass effect reducing bioavailability to 55%
after single doses
Multiple doses allow bioavailability to build up to 90%
Extensive tissue distribution
Extensively metabolized with 95% of dose being
excreted in the urine
Metabolites are not pharmacologically active
50% binds to plasma proteins; mainly albumin
Food reduces the rate of absorption but not extent
of absorption
Mechanism of action of RIMA’s
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Moclobemide
◦ Inhibitor and substrate
of P450-2C19 and
P450 2C9
◦ Inhibitor, substrate and
inducer of P-450 2D6
Moclobemide dosing
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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
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Dietary restrictions:
◦ Administering
Moclobemide after
ingestion of tyramine
containing foods reduces
potentiation of tyramine
◦ Limit intake of tyramine
containing foods, alcohol
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High rate of drug
interactions although
less than first generation
MAOI’s
Moclobemide Overdose
Nausea
 Drowsiness
 Mild disorientation
 Slurred speech
 Amnesia
 Reduced reflexes
 No organ toxicity
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Moclobemide Vs. Tranylcypromine
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Small quantities are
excreted in human
milk
Less drug interactions
and dietary
restrictions
Reversible and specific
No active metabolites
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Irreversible nonspecific
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
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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
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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.
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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-Dueñas, Fernando Cardozo-Pelaez, and Juan
R. Sánchez-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.
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Metabolism of harmala alkaloids
It has been found that CYP450 catalyze Odemethylation 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.
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Toxicity of Harmala alkaloids
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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: insecticide
MAOI
Also
inhibits prostaglandins, interacts
with octopamine receptors in CNS
Causes over excitation, paralysis, and
death in insects
Not very effect against mammals, used
in dog flea/mite infestation
Rapidly bio-transformed into six
metabolites in humans
Amitraz LD50’s
Resources

Baker, Glen B., Ronald T. Coutts, Kevin F. McKenna, and Rhonda L. Sherry-McKenna. "Insights into the Mechanisms of Action of the MAO Inhibitors Phenelzine and
Tranylcypromine: A
Review." Journal of Psychiatry and Neuroscience 17.5 (1992): 206-14. Pubmed. Web. 14 Mar. 2012.
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Bonivento, Daniele, Erika M. Milczek, G Reid McDonald, Claudia Binda, Andrew Holt, Dale E. Edmondson, and Andrea Mattevi. "Potentiation of Ligand Binding through
Cooperative Effects in Monoamine Oxidase B." Journal of Bioligical Chemistry 285.47 (2010): 36849-6856. Pubmed. Web. 13 Mar. 2012.

Bonnett, Udo. "Moclobemide "Therapeutic Use and Clinical Studies"" CNS Drug Reviews 9.1 (2003): 97-140. Wiley Online Library. Web. 18 Apr. 2012.
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2005. Print.
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Pharmacology
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McKim, William A. Drugs and Behavior: An Introduction to Behavioral Pharmacology. Upper Saddle River, NJ: Prentice Hall, 2003.
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Serrano-Dueñas, M, F Cardozo-Pelaez, and JR Sánchez-Ramos. "Effects Of Banisteriopsis Caapi Extract On Parkinson's Disease." Scientific Review Of
Alternative Medicine 5.3 (2001): 127-132. CINAHL Plus with Full Text. Web. 25 Apr. 2012
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Silva, Sara et al. Synthesis of New Monoamine Oxidase Inhibitors
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Villggier, Anne-Sophie, Brittney Gallager, Jon Heston, James D. Belluzzi, and Frances M. Leslie. "Age Influences the Effect of Nicotine and Monoamine Oxidase Inhibition
on Mood-related
Behaviors in Rats." Psychopharmacology 208 (2010): 593-601. Pubmed. Web. 13 Mar. 2012.

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psychotropic βcarboline alkaloids harmaline and harmine. J Pharmacol Exp Ther 305: 315–322.
Websites
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"DrugBank: Tranylcypromine.”DrugBank. Open Data Drug and Drug Target Database, 14 Feb. 2012. Web. 25 Apr. 2012. <http://www.drugbank.ca/>.
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"DrugBank: Moclobemide." DrugBank. Open Drug Data and Drug Target Database, 14 Feb. 2012. Web. 18 Apr. 2012. <http://www.drugbank.ca/>.
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Environmental Protection Agency. (1996). R.E.D. Facts – Amitraz. Prevention, Pesticides And Toxic Substances (7508W), November 1996
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Long, Phillip. "Moclobemide." Internet Mental Health. 2011. Web. 15 Apr. 2012. <http://www.mentalhealth.com/>.
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"Moclobemide." Medscape. WebMD, 2012. Web. 18 Apr. 2012. <http://reference.medscape.com/drug/moclobemide-342950#3>.
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Movement disorder virtual university Web 18. Apr. 2012. <http://www.mdvu.org/>
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"Parnate( Tranylcypromine)." Medscape. WebMD, 2012. Web. 18 Apr. 2012. <http://reference.medscape.com/drug/parnate-tranylcypromine-342952#10>.
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PubChem Substance. Amitraz – Substance Summary. Retrieved from http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=13178#x321