Week 3: Adrenergics II Flashcards
Tyrosine hydroxylase is highly regulated. How is this accomplished? (4 methods)
Phosphorylation of TH increases activity
During chronic stimulation, TH gene transcription –> more TH
End-product feedback inhibition decreases TH activity
Activation of phosphatases dephosphorylate TH, decreasing activity
What is unique about the formation of NE and the enzyme related to that step?
Dopamine-b-hydroxylase is located in the vesicular membrane, so dopamine is converted to NE as it enters the vesicle
How does the final step of EPI synthesis occur, and what enzyme mediates it?
Phenylethanolamine-N-methyltransferase (PNMT) uses S-adenomethionine (SAM) to add a methyl group onto the terminal NH2 group on NE
Why is L-DOPA used to treat Parkinson’s?
Dopamine, NE and EPI don’t cross membranes well, whereas L-DOPA (an amino acid), can easily cross into the CNS to form dopamine, NE and EPI as needed.
What is reserpine? What was it used for and why is it no longer used?
Reserpine mediates storage of NE in vesicles by blocking vesicular monoamine transporters (VMAT1 and/or 2). This caused side effects of depression and gastric ulcers. Inhibition of dopamine is likely what caused depression. The greater scope was an attempt to lower BP by decreasing NE/EPI secretion.
It was originally used to treat “madness” in Africa, and in the West to treat schizophrenia. It later became the first “modern” antihypertensive drug. It is no longer used because it’s effects were found to be too broad, and more specific, potent mediators have been discovered.
What is the method of inhibition of botulinum toxin? What negative effects can it generate, and what therapeutic effects can it have?
Botulinum toxin blocks the fusion of ACh-containing vesicles by hydrolyzing SNAP-25, leading to failure of release and, thus, neurotransmission at the NMJ. This can lead to respiratory paralysis and likely death.
At small doses, it can treat cerebral palsy, spasticity, and excess sweating.
At very small doses, it can be used to arrest facial muscle contraction and smooth out wrinkles, aka Botox!
What is the function of clonidine?
Stimulates presynaptic a2A and a2C adrenergic receptors, decreasing cAMP and resulting in hyperpolarization (decreased nerve firing). This results in the decreased release of NE. Clonidine acts as an anti-hypertensive.
What is the function and mechanism of amphetamines? What is it used to treat?
Amphetamines help release NE and prolong their actions in the SNS. In the CNS, it does the same thing for NE, dopamine and serotonin.
It is used to treat ADHD, narcolepsy, and is a general stimulant.
This is accomplished by Ca2+ (non-physiological) release of catecholamines, along with ephedrine and tyramine. Amphetamine blocks VMATs as well as MAOs, creating high [NE] in the presynaptic space. Excess NE is pumped out into the synaptic space in reverse, prolonging activation of receptors. Overall, amphetamines block reuptake of NE/dopamine and stimulate its release.
What is the function and mechanism of ephedrine? What is it used to treat?
Ephedrine weakly stimulates b1, b2 and a1 receptors. It relaxes bronchi, stimulates the heart, and raises BP. It is used to treat hypotension, myasthenia gravis, and asthma, and is an appetite suppressant.
This is accomplished by Ca2+-independent (non-physiological) release of catecholamines, along with tyramine and amphetamines.
What is the function and mechanism of tyramine? What is it used to treat?
Tyramine enters the nerve NE terminal and can displaced the NE from the cytoplasm. Some foods are high in tyramine, which is usually broken down by MAO. However, if someone is taking MAOIs, it can cause a significant increase in tyramine and a drastic increase in BP.
Along with ephedrine and amphetamines, it produces Ca2+-independent (non-physiological) release of catecholamines.
What is the mechanism for catecholamine-releasing drugs? What are these? Why can we develop physiological tolerance to them?
“TAPE C”
Amphetamines, Tyramine, Ephedrine, Pseudoephedrine, Cocaine
These drugs likely reverese the catecholamine reuptake pump, allowing for NE, EPI and dopamine to remain in the synapse for longer and activate the SNS.
Individuals can develop tolerance to thembecause there are alimited amount of catecholamines available for release, and therecan be desensitization or even decrease (down-reg) of receptors.
What is the function and mechanism of cocaine? Why do people abuse it? How do we know this, from use of desipramine?
Cocaine blocks reuptake of NE, serotonin and dopamine into the presynaptic terminal, thereby prolonging their actions in at nerve connections. The dopaminergic effects of cocaine is the primary addicting factor.
We know this because desipramine blocks NE reuptake and does not cause addiction, so the dopamine release and prolonged action (without reuptake) is what makes cocaine addicting.
What all can cocaine and amphetamines block in the CNS?
They block reuptake of NE, dopamine and serotonin by blocking NET (NE transporter), DAT (dopamine transporter), and SERT (serotonin transporter)
What is the function and mechanism of desipramine and other tricyclic drugs? Why are they not abused?
They selectively block NE re-uptake in the periphery and CNS. These drugs are not abused because they don’t affect dopamine secretion or reuptake.
What are the two major enzymes that break down catecholamines? How are they interrelated? What are the final products?
Both MAO (monamine oxidase) and COMT (catechol-o-methyl transferase) are involved in catecholamine breakdown. Either can be used in the first breakdown step, but these are interrelated because both are ultimately necessary to break down catecholamines.
VMA (vanillylmendelic acid) and MHPG (3-methoxy-4-hydroxy phenylglycol) are the major end products.
