Lecture 40 Flashcards
Sympathomimetics
Sympathetic NS
- Fight or flight
- Catecholamine receptors (NE, Epi, DA)
Monoamines
- Catecholamines
- Serotonin (indoleamine)
Serotonin
- Neurotransmitter in CNS
- Regulator of smooth muscle function in CV and GI
- Regulates platelet function
Catecholamines
- Endogenous neurotransmitters
- DA, NE, Epi, precursor: DOPA
- Isoproterenol - synthetic catecholamine
- Phenylethylamine - basic structure of catecholamines
Catecholamine Processes
- Synthesis
- Storage
- Release
- Uptake
- Metabolism
Catecholamine Synthesis
- Phenylalanine and Tyrosine = amino acid substrates for catecholamine synthesis
- Phenylalanine - essential AA, hydrolyzed by phenyl. hydroxylase to tyrosine
- Tyrosine - taken into neurons/adrenal cells and hydrolyzed at three positions by tyrosine hydroxylase into L-DOPA
L-DOPA - Synthesis
- Forms GABA, histamine, and serotonin
- Decarboxylated by aromatic L-AA decarboxylate to dopamine
Dopamine - Synthesis
- Stored in vesicles
- Converted into NE by dopamine B-hydroxylase
NE - Synthesis
Present in most postganglionic sympathetic NS
Chromaffin Cells -Synthesis
- Converts NE ==> Epi in adrenal gland
- Done by PNMT, induced by corticosteroids
- Stored in these cells’ granules for release
- Cofactor: S-Adenosylmethionine
Synthesis Regulation
-Tyrosine Hydroxylase is the rate limiting step
Regulated by:
- Acute, short term activation
- Chronic, long term activation
- End product feedback inhibition
Acute Activation
- Phosphorylation of tyr. hyd. be protein kinases
- Decreases the km of the enzyme for cofactor (tetrahydrobiopterin) more active
- Increases the synthesis of catecholamines
- Occurs in seconds/minutes and lasts minutes to hours
Chronic Activation
- Chronic stress can induce tyr. hyd.
- Initiation: increases in cAMP ==> Activates protein kinase A ==> Phosphorylates and activates CREB ==> enters nucleus/binds to DNA ==> increases expression of tyr. hyd.
- Prolonged, chronic stress causes this
End Product Inhibition
- All catecholamines inhibit tyr. hyd. activity
- Direct competition of catecholamines with cofactor tetrahydrobiopterin
Storage
- NE, DA, Epi ==> vesicles to nerves and adrenal (NE/Epi)
- Allows for immediate, controlled release
- Protect catecholamines from metabolism
- Vesicular uptake: ATP-dependent protein translocase, needs ATP to store
- Reserpine - inhibits VMAT transport which depletes catecholamines (irreversible)
Release
- Calcium dependent stress
- Calcium uptake cause vesicular attachment/release
- Increased activity of SNS increases the concentrations of NE, Epi, ATP, DBH, and chromogranins in circulation
- Two chromaffin granules: NE (20%) and Epi (80%)
Catecholamine Reuptake Categories
- Neuronal (Uptake 1)
2. Extraneuronal (Uptake 2)
Neuronal (Uptake 1)
- Primary terminator of catecholamine activity
- Sodium dependent, high affinity, isoproterenol = exception
- High affinity receptors for DA, 5-HT, and NE
- Monoamine transporters - 12 transmembrane domains
- Drug target: Fluoxetine (SSRIs), Desperimine (NE), Cocaine (DA, NE, 5-HT
Extraneuronal (Uptake 2)
- Low affinity for NE/Epi, high affinity for isoproterenol
- Present in glial, hepatic, myocardial, and other cells
- Removes CIRCULATING catecholamines
Indirect Acting Sympathomimetics
- Work via uptake pumps
- Tyramine and Ephendrine (also act on B2 receptors)
- Taken up by transporters and indirectly release NE
- Compete for transporter space to enter vesicle and facilitate exchange diffusion by making carrier available
Nonvesicular Release
Calcium not needed, no ATP/DBH released
Tachyphylaxis
-Repeated tyramine administration, decreases postsynaptic response
Due to:
- Depleting vesicular NE
- Replacing NE with octopamine (false neurotransmitter)
Metabolism - Enzyme Types
- MAO
2. COMT
MAO
- Removes N from monoamines
- High concentrations in liver, kidneys, and MA neurons
- On mitochondria surface in nerve terminal
- Isoforms: MAO-A and MAO-B
- Metabolizes catecholamines released intraneurally and ones taken back into the neuron
- Inhibitors play a role to potentiate catecholamine effect
- Parkinsons: MAO/COMT inhibition increases dopamine/L-DOPA activity
MAO-A
- Prefers 5-HT and NE
- Inhibited by Tranylcyromine (Parnate) - used for depression, inhibits A & B, irreversible
MAO-B
- Prefers dopamine
- Selegiline inhibits it - used for Parkinson’s, irreversible
COMT
- Methylates catecholamines at 3 ring positions
- Located in liver, kidney, and BBB
- Catecholamines that enter endo/exogenously are first metabolized by this
- Inhibitor: Tolcaponel (Tasmar) and Entacapone - adjunct therapies for Parkinson’s (inhibits DOPA metabolism)
Beta 1
- Near regions of nerve terminals
- Increases HR and contraction
- Increases renin release by kidney
- Increases lipolysis
- Dobutamine - agonist
- Metoprolol - antagonist
Beta 2
- Smooth muscle relaxation (lungs, blood vessels, uterus)
- Gluconeogenesis/glycogenolysis
- Away form nerve terminals, adrenal Epi release via blood
- Terbutaline - agonist