| How are sympathetic neurons? | Preganglionic come from thoracic and lumbar regions of spinal cord, synapse in ganglia and run parallel on each side of the cord, preganglionic neurons are shorter than post-ganglionic neurons, which extend to tissues they innervate and regulate. |
| What are adrenergic neurons? | Release NE as primary neurotransmitter, found in CNS and sympathetic nervous system, links between ganlgia and effector organs act on adrenergic receptors presynaptic/postsynaptic on the effector organs |
| How is the mechanism of neurotransmission by adrenergic neurons? | Synthesis of NE, Storage of NE in vesicles, Release of NE, Binding to receptors, Removal from synaptic cleft with potental fates of recaptured NE. |
| How is synthesis of NE? | Tyrosine goes to adrenergic neuron by Na+ linked carrier where it gets hydroxylated by DOPA into tyrosine hydroxylase (rate-limiting step)
DOPA then decarboxylates to form dopamine in cytoplasm of presynaptic neuron |
| How is storage of NE in vesicles? | Dopamine then is transported to vesicles by amine transporter involved also in reuptake of NE, this carrier system is blocked by reserpine, dopamine then is hydroxylated to form NE by enzyme dopamine beta-hydroxylase.
Then NE is methylated to make Epi both of which are stored in chromaffin cells of adrenal medulla, with stimulation medulla releases 80% Epi and 20% NE into circulation |
| How is release of NE? | AP reaches nerve junction, triggers influx of Ca ions from ECM to neuron, increased Ca fuses vesicles with membrane and exocytose NE, this is blocked by Guanethidine and Bretylium. |
| How is binding to adrenergic receptors of NE? | NE diffuses through synaptic cleft, reaches the receptors bind to effector organ/ presynaptic nerve ending, this triggers a cascade of events like second messengers use cAMP system/ phosphatydilinositol to transduce the signal into an effect. |
| How is removal of NE? | Norepinephrine may:
1) diffuse out of the synaptic space and enter the general circulation,
2) be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space,
3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron
The uptake by the neuronal membrane involves a sodium/potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine
Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine’s effects |
| What are potential fates of recaptured NE? | May get taken up by adrenergic vesicles via amine transporter system and get sequestered for another release, or can be oxidized by MOA in neuronal mitochondria which inactivates it and releases it into urine as Vanylilmadilic acid and normetanephirne |
| How are adrenergic receptors? | two families a and b according to response to NE, epi and isoproterenol. |
| How are alpha adrenergic receptos responses? | The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine.
For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. |
| How are alpha adrenergic receptors affinity? | two subgroups a1 and a2 for agonist and antagonist respectively.
a1 higher affinity for phenylephrine and NE, while a2 more affinity for clonidine |
| How are alpha 1 adrenergic receptors? | Location (post-synaptic membrane of effector organs, mediate classic effects)
Second messenger (G protein activation of phospholipase C resulting in formation of inositol triphosphate (IP3) and DAG from phosphatydilinositol. |
| How are a2 adrenergic receptors? | Location (presynaptic nerve endings, on other cells like b cells of pancreas, control neuromediator and insulin output respectively. stimulation gives feedback inhibition of ongoing release of NE from stimulated adrenergic neurons, inhibitory action decreases further output of adrenergic neurons and serves as a local modulation mechanism for reducing sympathetic neuromediator output when high sympathetic activity. They are also found in presynaptic parasympathetic neurons)
Second messenger (inhibition of adenylyl cyclase and decrease in intracellular cAMP) |
| How are beta receptors? | Affinity (strong response to isoproterenol less sensitive to NE and EPI iso>epi>NE three subgroups b1, b2 and b3 based on affinity and response)
Responses (b1 equal affinity to NE and Epi, b2 higher for epi seen in skeletal muscle vasculatures respond to hormonal effects of circulating EPI by adrenal medulla)
Second messengers (activate adenylyl cyclase increases cAMP |
| How is distribution of adrenergic receptors? | Organs and tissues tend to have a predominance of a single type of receptors (vasculature of skeletal muscles b2 receptors predominate, heart contains b1 receptors)
Some tissues may have only one type of receptor exclusively |
| What are characteristic responses mediated by adrenoreceptors? | . |
| What is desensitization of receptors? | Prolonged exposure to the catecholamines reduces the responsiveness of these receptors
Three mechanisms have been suggested to explain this phenomenon:
sequestration of the receptors so that they are unavailable for interaction with the ligand;
down-regulation: disappearance of the receptors either by destruction or decreased synthesis;
an inability to couple to G protein, because the receptor has been phosphorylated on the cytoplasmic side |
| What is tachyphylaxia? | Repetitive exposure of a receptor to an agonist leads to desensitization and then diminished effect due to the agonist
Receptors are in the surface but less responsive. |
| What is downregulation? | Internalized receptors due to high agonist concentration, these may be recycled, restored or processed and degraded decreasing the total number of receptors |
| What are the characteristics of catecholamine adrenergic agonists? | High potency
Rapid inactivation (metabolized by COMT postsynaptic and MAO intraneuronal, brief period of AP given PRL, ineffective if given oral)
Poor penetration into CNS (polar, some have clinical effects like anxiety, tremor, and headaches) |
| What are characteristics of non-catecholamine adrenergic agonists? | lack catechol hydroxyl group, longer half-life not inactivated by COMT, phenylephrine, ephedrine and amphetamine.
Phenylephrine analogue of epi, ephedrine has methyl substitute.
They are poor substrates for MAO, prolonged duration of action, increased lipid solubility greater CNS penetration |
| What are substitutions on amine nitrogen? | The nature and bulk of the substituent on the amine nitrogen is important in determining the β selectivity of the adrenergic agonist.
For example, epinephrine, with a –CH3 substituent on the amine nitrogen, is more potent at β receptors than norepinephrine, which has an unsubstituted amine.
Similarly, isoproterenol, with an isopropyl substituent –CH(CH3)2 on the amine nitrogen is a strong β agonist with little α activity |
| What are mechanisms of action of adrenergic agonists? | 1. Direct-acting agonists:
act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla epinephrine, norepinephrine, isoproterenol, and phenylephrine.
2. Indirect-acting agonists:
may block the uptake of norepinephrine (uptake blockers) cocaine, cause the release of norepinephrine from the vesicles of the adrenergic neuron (tyramine) amphetamine and tyramine
3. Mixed-action agonists:
stimulate adrenoceptors directlyand stimulate the release norepinephrine from the adrenergic neuron ephedrine, pseudo-ephedrine and metaraminol, |
| How are classifications of adrenergic agonists? | . |
