Agents acting on the Biosynthesis, Storage, Release and Elimination of Catecholamines Flashcards by Maria Haslacher

Overview of the Sympathetic Efferent System

Preggl neuron: ACh–> ggl
Post ggl neuron (nor)adrenergi neuron–> NA to innervated tissue

Preggl neuron: ACh-> Adrenal Medulla
Adrenal Medulla then releases A, NA

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Biosynthesis of NA and other Catecholamines

Tyrosine– Tyrosine hydroxylase–> DOPA

DOPA—DOPA decarboxylase–> Dopamine

Dopamine– Dopamine b hydroxylase–> NA

NA– Phenylethanolamine N-methyltransferase–> Adrena.

Phenylethanolamine N-methyltransferase: found in Adrenal Medulla

Endogenous catecholamines:
Dopamine, NA, Adrenaline

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Enzymes of Catecholamine Biosynthesis

Tyrosine hydroxylase

Cytosolic
Rate limiting
Subject to end product inhibition

L-tyrosine is actively taken up into adrenergic nerve ending for this

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Enzymes of Catecholamine Biosynthesis

DOPA decarboxylase

Cytosolic
Non specific

Also involved in histamine and 5HT synthesis

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Enzymes of Catecholamine Biosynthesis

Dopamine b hydroxylase

Vesicular
Released during AP induced exocytosis but not taken up

–> Indicator of sympathetic activity

Inhibited by disulfiram

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Enzymes of Catecholamine Biosynthesis

Phenylethanolamine N-methyltransferase

Found in Adrenal Medulla and Brain

Induced by cortisol

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Drugs Influencing Catecholamine Biosynthesis

a- Methylthyroxine

Taken up actively -> NA nerve endings and adrenal medulla

Inhibits tyrosine hydroxylase-> diminishes synthesis of NA and Adrenaline

Used in phaeochromocytoma th

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Drugs Influencing Catecholamine Biosynthesis

L-DOPA

Used to replace deficient dopamine in Parkinsons

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Drugs Influencing Catecholamine Biosynthesis

Carbidopa, Benserazide

DOPA decarboxylase inhibitors

Don’t enter CNS
Co-applied with L-DOPA to decrease its peripheral SEs

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Drugs Influencing Catecholamine Biosynthesis

a-Methyldopa

Taken up actively into NA nerve endings

Acts as false/alternative substrate for DOPA decarboxylase–> forms a-methyldopamine: alternative substrate for dopamine-b-hydroxylase–> a-methylNA

In addition, less NA is produced due to competition

a-methylNA is a false NT:
higher affinity to a2 R and less effect at a1 R compared
to NA–> reduced exocytotic transmitter release via
prejunctional a2 R

a-methylNA is also formed in central NA neurons
Diminishes activity of vasomotor center via a2 R
–> central sympatholytic

Decrease BP
Rarely used as antihypertensive due to SEs
No evidence for teratogenicity: used in pregnant patients

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Vesicular Storage of NA

NET transports NA from synaptic cleft-> cytosol
NE/Na symporter
Here some NE is degraded by MAO

VMAT accumulates NA in vesicles: NE in; H out
–> 2ary active H-monoamine antiporter
Driven by H ATPase (H into cell): actively accumulates H
in cell

VMAT can also accumulate dopamine, serotonin

VMAT isoforms
VMAT1: NA sympathetic nerve endings (peripheral)
VMAT2: monoaminergic neurons of CNS

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What is stored in the vesicles

NA stored with ..... in vesicles
   dopamine
   dopamine b hydroxylase
   chromogranin A
   ATP (co transmitter)

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Drugs Affecting NA Storage

Reserpine

Irreversible inhibitor of VMAT 1 and VMAT 2

Enters nerve ending via diffusion
Inhibits vesicular uptake of dopamine and NA
–> both are metabolised by MAO

Effect: depletion of NA and dopamine in nerve endings

Can also cause transmitter depletion in (Nor)adrenergic, dopaminergic, serotinergic neurons in CNS–> sedation, parkinsonism, depression

Historical use: Th of hypertension

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Drugs Affecting NA Storage

Tetrabenazine

VMAT 2 Inhibitor

Used in Huntington’s Chorea

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Drugs Affecting NA Storage

Indirectly acting sympathomimmetics
Adrenergic neuron blockers

Are alternative substrates for VMAT

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Physiological Mechanism of NA release

AP–> Opening of voltage gated Ca channels–> Ca influx to adrenergic nerve ending–> Exocytosis

Releasing all components of vesicular contents

–> AP and Ca dependent

Function of prejunctional a2 R

Negative feedback
Gi
Inhibit adenylate cyclase and opens K channel
No production of cAMP
No Ca channel opening

Prejunctional Rs Controlling AP Induced Exocytotic NA Release

Inhibiting NA release

Adrenergic a2 R
Opioid Rs
M2 Muscarinic R
Adenosine A1 R
Serotonin 5-HT1 R

Enhancing NA release (Gs or Gq coupled)
Adrenergic b2 R
Angiotensin II AT1 R

MoA of Indirectly Acting Sympathomimetics

Enter cytoplasm of (nor)adrenergic nerve endings as alternative substrates for uptake-1 (NET)
Are chemically similar to NA

Taken up into vesicles as alternative substrates for VMAT (in exchange of only NA not dopamine)

NA in cytosol: partly degraded by MAO
Mainly via reversed action of uptake-1: released
Stimulates a1, a2, b1 R

Tachyphylaxis develops: NA pool is depleted

Indirectly Acting Sympathomimetics

Amphetamin and its Derivatives

Peripheral sympathomimmetic effect

Also have strong psychomotor stimulant and appetite reducing effect via release of monoamines in brain

Highly abusive

Indirectly Acting Sympathomimetics

Ephedrine

Also has direct b R agonistic effect
therefore mixed sympathomimmetic

Slight psychomotor stimulant and appetite reducing effect

As sympathomimmetic:
used to treat nasal congestion, hemorrhoids,
hypotension
used to produce mydriasis

Indirectly Acting Sympathomimetics

Tyramine

High amounts in red wine and cheese

Oral bioavailability limited by MAO-A metabolism in gut and liver

If combo with an MAO-A inhibitor-> increased bioavailability-> hypertensive crisis (cheese reaction)

Drugs Inhibiting Release of NA: NA Neuron Blocking Agents

Enter cytoplasm of NA nerve endings as alternative substrates for uptake-1

Accumulate, block voltage gates Na channels in membrane-> prevent propagation of AP-> inhibit exocytosis

Another theory
Enter vesicles as alt. substrates for VMAT1-> inhibit
exocytosis directly (unclear mechanism)

Overall effect: inhibition of AP induced exocytotic NA (and other in vesicles stored stuff) release-> general sympatholytic

Have 2 additional effects
1) IV admin: may transiently increase NA release by
reverse operation of uptake-1–> tyramine like indirect
sympathomimmetic action

2) Competitively inhibit transport of NA and dopamine
into vesicles-> promote MAO med. breakdown–>
slowly developing NA depleting, reserpine like effect

Enhance effect of exogenously applied catecholamines by competitive inhibition of uptake-1

NA Neuron Blocking Agents

Bretylium, Guanethidine, Guanadrel, Bethanidine

Hydrophylic compounds-> poor oral absorption
Don’t enter brain-> no CNS effect

SE
   Orthostatic hypotension
   Water retention
   Diarrhoea
   Ejaculation failure
   Nasal congestion

Only historical use: treatment of hypertension

Guanethidine eyedrops: used to decrease IO pressure in glaucoma (reduction of aqueous humor prod.)

Bretylium (prototype)
Additionally blocks voltage gates K channels in heat
–> antiarrythmic effect

Effect of Cocaine on Uptake-1

Uptake-1 Symport NA/Na Driven by Na/K ATPase produced conc. gradient Cocaine inhibits Uptake-1

Elimination Mech of Catecholamines Uptake

Uptake-1 NET: NA transport from cleft-> cytoplasm Similar Na- monoamine Symporters exist for dopamine (DAT) and serotonin (SERT) in monoaminergic CNS neurons Uptake-2 Extra monoamine transporter (EMT) of NA, dopamine, serotonin into SM, endothelial, glial cells Also a secondary active transporter

Direct Comparison of Uptake ``` Capacity Affinity Specificity Localisation Alt. Substrates Inhibitors ```

``` Uptake 1: Capacity: small Affinity: high Specificity: NA>adrenaline>dopamine Localisation: neuronal Alt. Substrates: Ind. acting sympathomimmetics adrenergic neuron blocking drugs Inhibitors: cocaine, TCA ``` Uptake 2: Capacity: high Affinity: high Specificity: adrenaline>NA>isoprenaline Localisation: SM, endothel, glial cells Alt. Substrates: dopamine, 5HT Inhibitors: glucocorticoids (-> potentiation of circulating Adrenaline)

Monoamine Oxidase

Performs oxidative deamination Converts NA/Adrenaline-> DOPGAL Converts normetanephrine or metanephrine-> MOPGAL Bound to external membrane of mitochondria Also metabolises dopamine and serotonin in dopaminergic and serotonergic neurons in CNS

Monoamine Oxidase

Types of MAO

MAO-A Noradrenergic nerve terminals, liver, CNS, adrenal medulla, gut wall Prefers NA> 5HT> dopamine MAO-B Only predom in CNS neurons Prefers dopamine> NA MAO Inhibitors are used as antidepressants (MAO-A) or antiparkinsonian (MAO-B) drugs

Aldehyde Reductase

Reduces DOPGAL-> DOPEG Reduces MOPGAL-> MOPEG Found in (nor)adrenergic nerve terminals and adrenal medulla

Catechol-O-Methyltransferase: COMT

Methylates OH group on C3 in NA, adrenaline, DOPEG, DOMA Found in several tissues but not in noradrenergic nerve endings

Catechol-O-Methyltransferase: COMT

Methylates OH group on C3 in NA, adrenaline, DOPEG, DOMA Found in several tissues but not in noradrenergic nerve endings Inhibition doesn't affect noradrenergic transmission COMT Inhibitors; used in Parkinsons Entacapone Tolcapone

Alcohol dehydrogenase

Found in liver | Converts MOPEG -> MOPGAL

Aldehyde Dehydrogenase

Found in liver Converts MOPGAL-> vanillylmandelic acid (VMA) Converts DOPGAL-> DOMA Also involved in breakdown of dopamine and serotonin

Sulfotransferase

Found in gut wall | Sulfates MOPEG and metanephrine

Fate of Endproducts of NA and Adrenaline Breakdown

Excreted in urine Phaeochromocytoma: VMA is increased