Agents acting on the Biosynthesis, Storage, Release and Elimination of Catecholamines Flashcards
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
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
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
Enzymes of Catecholamine Biosynthesis
DOPA decarboxylase
Cytosolic
Non specific
Also involved in histamine and 5HT synthesis
Enzymes of Catecholamine Biosynthesis
Dopamine b hydroxylase
Vesicular
Released during AP induced exocytosis but not taken up
–> Indicator of sympathetic activity
Inhibited by disulfiram
Enzymes of Catecholamine Biosynthesis
Phenylethanolamine N-methyltransferase
Found in Adrenal Medulla and Brain
Induced by cortisol
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
Drugs Influencing Catecholamine Biosynthesis
L-DOPA
Used to replace deficient dopamine in Parkinsons
Drugs Influencing Catecholamine Biosynthesis
Carbidopa, Benserazide
DOPA decarboxylase inhibitors
Don’t enter CNS
Co-applied with L-DOPA to decrease its peripheral SEs
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
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
What is stored in the vesicles
NA stored with ..... in vesicles dopamine dopamine b hydroxylase chromogranin A ATP (co transmitter)
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
Drugs Affecting NA Storage
Tetrabenazine
VMAT 2 Inhibitor
Used in Huntington’s Chorea
Drugs Affecting NA Storage
Indirectly acting sympathomimmetics
Adrenergic neuron blockers
Are alternative substrates for VMAT
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
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
Inhibition of MAO-> increased NA, dopaminergic, serotonergic transmission
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
