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Pharma 1 > Agents acting on the Biosynthesis, Storage, Release and Elimination of Catecholamines > Flashcards

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

1
Q

Overview of the Sympathetic Efferent System

A

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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2
Q

Biosynthesis of NA and other Catecholamines

A

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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3
Q

Enzymes of Catecholamine Biosynthesis

Tyrosine hydroxylase

A

Cytosolic
Rate limiting
Subject to end product inhibition

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

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4
Q

Enzymes of Catecholamine Biosynthesis

DOPA decarboxylase

A

Cytosolic
Non specific

Also involved in histamine and 5HT synthesis

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5
Q

Enzymes of Catecholamine Biosynthesis

Dopamine b hydroxylase

A

Vesicular
Released during AP induced exocytosis but not taken up

–> Indicator of sympathetic activity

Inhibited by disulfiram

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6
Q

Enzymes of Catecholamine Biosynthesis

Phenylethanolamine N-methyltransferase

A

Found in Adrenal Medulla and Brain

Induced by cortisol

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7
Q

Drugs Influencing Catecholamine Biosynthesis

a- Methylthyroxine

A

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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8
Q

Drugs Influencing Catecholamine Biosynthesis

L-DOPA

A

Used to replace deficient dopamine in Parkinsons

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9
Q

Drugs Influencing Catecholamine Biosynthesis

Carbidopa, Benserazide

A

DOPA decarboxylase inhibitors

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

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10
Q

Drugs Influencing Catecholamine Biosynthesis

a-Methyldopa

A

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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11
Q

Vesicular Storage of NA

A

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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12
Q

What is stored in the vesicles

A 
NA stored with ..... in vesicles
   dopamine
   dopamine b hydroxylase
   chromogranin A
   ATP (co transmitter)
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13
Q

Drugs Affecting NA Storage

Reserpine

A

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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14
Q

Drugs Affecting NA Storage

Tetrabenazine

A

VMAT 2 Inhibitor

Used in Huntington’s Chorea

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15
Q

Drugs Affecting NA Storage

Indirectly acting sympathomimmetics
Adrenergic neuron blockers

A

Are alternative substrates for VMAT

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16
Q

Physiological Mechanism of NA release

A

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

Releasing all components of vesicular contents

–> AP and Ca dependent

17
Q

Function of prejunctional a2 R

A 
Negative feedback
Gi
Inhibit adenylate cyclase and opens K channel
No production of cAMP
No Ca channel opening
18
Q

Prejunctional Rs Controlling AP Induced Exocytotic NA Release

A

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

19
Q

MoA of Indirectly Acting Sympathomimetics

A

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

20
Q

Indirectly Acting Sympathomimetics

Amphetamin and its Derivatives

A

Peripheral sympathomimmetic effect

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

Highly abusive

21
Q

Indirectly Acting Sympathomimetics

Ephedrine

A

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

22
Q

Indirectly Acting Sympathomimetics

Tyramine

A

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)

23
Q

Drugs Inhibiting Release of NA: NA Neuron Blocking Agents

A

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

24
Q

NA Neuron Blocking Agents

Bretylium, Guanethidine, Guanadrel, Bethanidine

A

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

25
Q

Effect of Cocaine on Uptake-1

A

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

Cocaine inhibits Uptake-1

26
Q

Elimination Mech of Catecholamines

Uptake

A

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

27
Q

Direct Comparison of Uptake

Capacity
Affinity
Specificity
Localisation
Alt. Substrates
Inhibitors
A 
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)

28
Q

Monoamine Oxidase

A

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

29
Q

Monoamine Oxidase

A

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

30
Q

Types of MAO

A

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

31
Q

Aldehyde Reductase

A

Reduces DOPGAL-> DOPEG
Reduces MOPGAL-> MOPEG

Found in (nor)adrenergic nerve terminals and adrenal medulla

32
Q

Catechol-O-Methyltransferase: COMT

A

Methylates OH group on C3 in NA, adrenaline, DOPEG,
DOMA

Found in several tissues but not in noradrenergic nerve endings

33
Q

Catechol-O-Methyltransferase: COMT

A

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

34
Q

Alcohol dehydrogenase

A

Found in liver

Converts MOPEG -> MOPGAL

35
Q

Aldehyde Dehydrogenase

A

Found in liver
Converts MOPGAL-> vanillylmandelic acid (VMA)
Converts DOPGAL-> DOMA

Also involved in breakdown of dopamine and serotonin

36
Q

Sulfotransferase

A

Found in gut wall

Sulfates MOPEG and metanephrine

37
Q

Fate of Endproducts of NA and Adrenaline Breakdown

A

Excreted in urine

Phaeochromocytoma: VMA is increased

Pharma 1 (15 decks)

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