Adrenergic Transmission And Its Presynaptic Modification Flashcards
What are sympathomimetics?
they are adrenergic drugs that act directly on adrenergic receptors by activating them
What are sympatholytics?
Adrenergic drugs that block the action of the NT at there receptor or they can interrupt the release of NE from adrenergic neurons
What is the rate limiting step of NE synthesis?
tyrosine hydroxylase
What is the co-factor of tyrosine hydroxylase?
Vit C
What is the mechanism of action of Reserpine?
It inhibits VMAT2
What is the mechanism of action of Guanethidine?
It inhibits the release of vesicles containing NE into the synaptic cleft
What is NET?
It is the Na+/Cl- dependent NE transporter
What inhibits NET?
TCA e.g., Imipramine
Serotonin-NE reuptake inhibitors e.g., duloxetine, cocaine
What is the action of methyl-p-tyrosine?
Inhibits tyrosine hydroxylase
What is the mechanism of action of MAO inhibitors?
it leads to increased NE in the mobile pool
What is the result of releasers?
it leads to the release of NE from the mobile poo.
What is the effect of an alpha 2 agonist on the pre-synaptic neuron?
Negative feedback
Reduced NE in the synapse
What is the effect of an alpha 2 antagonist on the pre-synpatic neuron?
Prevention of negative feedback
Increased NE synthesis and release
Both the skeletal muscles and vasculature have alpha and beta receptors, which predominates?
Beta receptors
What is desensitisation of adrenergic receptors?
Prolongued exposure to catecholamines leads to decreased responsiveness of these receptors
What are the possible mechanisms of desensitisation of adrenergic receptors?
- Sequestration of the receptors so that they are unavailable for interaction with the ligand
- Down regulation
- Inability to couple to H protein because the receptor has been phosphorylated on the cytoplasmic side
What is the result of OH substitutions in the 3rd and 4th position of the benzene ring?
Increased potency
Decreased absorption and distribution of the drugs
decreased lipophility
What are the characteristics of catechomaines with 3,4-IH substituents?
Most potent sympathomimetics
Bad pharmacokinetics: poor absorption, bad distribution, short duration of action.
They must be given parenterally for systemic use - they don’t penetrate the BBB
They are substrates of COMT, this further decreases their bioavailability
What are the characteristics of 3-OH, 4-OH or 3,5-OH derivatives?
Weaker sympathomimetics than the catecholamines but they have better pharmacokinetics
They are not substrates of COMT, but still polar drugs - they may be given orally with low bioavailability
What are the characteristics of non-substituted derivatives?
They have no hydroxyl groups
Very weak direct or only indirect (NE releasing) sympathomimetic action (bad pharmcodynamics)
They have very good pharmacokinetics: good absorption and penetration through the BBB (resulting in CNS effects)
What are the possible substitutions on the amino group?
Methylation
Large substitution
What is the effect of methylation on the amino group?
Methylation increases the relative potency on the Beta 2 receptors (NE/EPI)
What is the effect of large substitution of the amino group?
Large substitution on the amino group increases significantly the beta 2 receptor affinity
What is a precursor substance of adrenergic synthesis?
Levodopa
Name the reuptake inhibitors
Cocaine
TCA
Amitryptyline
Desipramine
Name the MAO inhibitors
Tranylcypromine
Selegiline
Moclobemid
What are the side edicts of guanethidine and debrisoquine?
Orthostatic hypotension Diarrhoea Impaired Ejaculation Sodium and Water retention Nasal Stuffiness Upregulation of postsynaptic receptors
What is the clinical indication of Guanethidine and Debrisoquine?
Hypertension
Limited use because of their side effects
What is the mechanism of action of Bretylium?
Acts like Guanethidine in NE nerve terminals It blocks K+ channels on the heart (a class 3 anti-arrhythmic action)
What is the clinical use of Bretylium?
Antiarrhythmic indication
How is Bretylium administered?
IV in emergency during resuscitation from ventricular fibrillation after lidocaine and cardioversion
What are the adverse effects of Bretylium?
Initial release of NE can lead to ventricular arrhythmias Sympatholytic action (e.g., orthostatic hypertension)
What is the mechanism of action of reserpine?
Blocks the uptake of biogenic amines into the synaptic vesicles. they are not stored in the vesicles and thus broken down by MAO
What are the theoretical indications of Reserpine?
Hypertension
Psychosis
What are the main side effects of Reserpine?
Sympatholytic actions (diarrhoea, postural hypotension: NE depletion in the periphery) Mental depression (NE and serotonin depletion in the CNS) Parkinsons (dopamine depletion in the nigrostriatal system)
What is the effect of alpha-methyl-tyrosine?
Blocks the tyrosine hydroxylase enzyme, no NE synthesis, decreased alpha and beta stimulation
What are the clinical indications of alpha-methyl-tyrosine?
May act synergistically with phenoxybenzamene in the treatment of pheochromocytoma
What is the mechanism of action of Tetrodotoxin, Saxitoxin and local aesthetics?
Blocks voltage sensitive Na+ channels
What is the mechanism of action of w-Conotoxin?
Blocks calcium channels
What is the action of 6-OH-dopamine?
Destroys the nerve terminal
