Introduction to Autonomic Pharmacology Flashcards
Recall that the sympathetic system originates in ________ distribution of the spinal cord, whereas the parasympathetic system originates in the ________ distribution.
Thoracolumbar
Craniosacral
Para v Snymp Fiber Lengths and Ganglion Position
The sympathetic system consists of short preganglionic fibers (paraspinal) and a long post-ganglion fibers. In contrast, the parasympathetic system has a very long pre-ganglionic fibers and short postganglionic fibers.
Thus, the sympathetic ganglia are located far from the target organ and the parasympathetic ganglia are located near the target organ.
Both para and symp use what neurotransmitter for preganglionic
Acetylcholine
Neurotransmitter for postganglionic of para and symp
Para: Acetycholine
Symp: norepinephrine, exceptions being in the adrenal medulla and at sweat glands
Parasympathetic is a ______ system
Sympathetic is a ________ system
Trophotropic (leads to growth)
Ergotrophic (energy expendature)
Blood vessels are mainly controlled by:
Mainly sympathetic
There are parasympathetic responsive receptors in blood vessels but rather than response to acetylcholine, these receptors respond to release of nitric oxide (a potent vasodilator).
Sympathetic and Para actions on gut and bladder
Symp: In the bladder, detrusor muscle relaxation and sphincter contraction. The same occurs within the gut, the sympathetic system causes decreased smooth muscle contraction in the GI system and contraction of the anal sphincter muscles.
Para: relaxation of the sphincter, contraction of the detrusor and increased motility and gut contraction
How does dilation and contraction of the pupil work?
How does accomodation of the lens occur?
Pupil: The pupil is controlled by two muscles of the iris, the radial muscle and the circular muscles. When the radial muscle is contracted, the pupil dilates or exhibits mydriasis (like blinds opening). When the circular muscle is contracted, the pupil becomes constricted or exhibits miosis (like purse string)
Lens: The zonular fibers act to pull the lens taught for distance vision. When the ciliary body fibers contract, zonular fibers relax their pull on the lens and allow it to plump out for near vision.
Autonomics of the eye
Pupil: Sympathetic leads to mydriasis (contraction of radial muscles), parasympathetic leads to miosis (contraction of circular muscles)
Lens: Sympathetic opposes the ciliary bodies, leading to zonular muscles pulling lens taught (distance). Parasympathetic encourages contraction of ciliary bodies, leading to accomodation
What is an agonist? Indirect Agonist?
Agonist: increase the effects at a certain synapse. Direct stimulation of receptor
Indirect Agonist: increase the downstream effects at a synapse through the release and removal sites. This is by either increasing the amount of neurotransmitter released from the presynapse or preventing its metabolism once it has been released into the synapse
Antagonist? Indirect antagonism?
Antagonist: direct blockade at the receptor itself
Indirect anatagonist: decreases the downstream effects of a synapse by some other means along the neurotransmission pathway
What is down regulation of receptors?
If there is axcess agonist, the number of receptors will be fall, untill excess is removed and then number of receptrs can increase to normal
What happens in chronic blockade?
The rate limiting step of adrenergic synthesis is
the conversion of tyrosine to DOPA by the enzyme tyrosine hydroxylase.
What is DOPA?
dihydroxypheylalanine, is the basis of ALL catecholamine neurotransmitters, i.e. norepinephrine, epinephrine, and dopamine. It is important to mention here that DOPA can pass through the blood brain barrier, but its later products are unable to.
The synthesis of catecholamine neurotransmitters
Adrenergic receptor target and action (as well as GPCR action)
What is unique about alpha 2 adrgenergic receptors?
Alpha 2 do negative feedbacl. α-2 receptors are typically found on the pre-synapse. They decrease cyclic AMP as a negative feedback system. Catecholimines are released from their vesicles into synapse and bind to these receptors on the pre-synaptic ganglion, letting them know it is time to slow down the release, “look there is plenty here!”
n general, the α-1 (alpha one) receptors do what
smooth muscle contraction in response to sympathetic stimulation.
The ß-1 (beta one) receptors do what
They are specific to the heart and kidney.
They are pharmacologically targeted for their effects on the heart which include increased conduction through the SA node and AV node and increased contractility in the atria and ventricles. In the kidney, ß-1 receptor stimulation causes release of renin from the juxtaglomerular apparatus. This action ultimately triggers the angiotension system and will lead to vasoconstriction.
The ß-2 (beta two) receptors do what
Smooth muscle relaxation (often in blood vessels, bronchioles, and bladder)
In terms of metabolism, catecholamines are metabolized by two important enzymes
MAO (monoamine oxidase) and COMT (catechol-o-methytransferase)
MAO removes and amine, COMT does methylation of hydroxyl groups
The final blood and urinary metabolite after both MAO and COMT conversion
VMA (3-methyoxy, 4-hydroxy mandelic acid) for epinephrine and norepinephrine and HVA (homovanillic acid) for dopamine.
Drug that blocks adrenergic synthesis
Metyrosine which inhibits the enzyme tyrosine hydroxylase and prevents production of catecholamines, thus depleting amount released at synapse.
Storage of adrenergic neurotransmitters can be inhibited by (drug)
Reserpine through blockade of the vesicular monoamine transporter that transports catecholamines into their pre-synapic vesicles. Un-vesicled and un-protected neurotransmitters are quickly metabolized by intracellular enzymes
Adrenergic Release can be disrupted through (drug)
Guanethidine can disrupt release through it’s action as a “false neurotransmitter.” After being taken up into the presynaptic terminal, it competes with catecholamines for vesicular storage and is alternatively released into the synapse instead of the intended neurotransmitter (will not bind to receptor or cause desired downstream effect).
Adrenergic Reuptake can be blocked by (drug)
Cocaine and Tricyclic Antidepressants act on the pre-synaptic reuptake receptors to salvage neurotransmitters after their release into the synapse. By causing a blockade on these re-uptake receptors, feel good catecholamines such as dopamine are allowed a prolonged stay in the synapse, causing the desired high or pharmacological effect.
The rate limiting step in cholinergic neurotransmission is
the uptake of choline into the synapse
Steps for acetylcholine synthesis
M1 (muscarinic type one) receptors function
predominately located in the stomach and enteric system, so their stimulation should lead to increased secretions along the GI tract. Think salivation, stomach acid secretion, and gallbladder secretion. We additionally find these receptors in the smooth muscle of the lungs where their activation will lead to bronchoconstriction.
M2 (muscarinic type two) receptors function
located in the heart. In contrast to the β-1 receptors in adrenergic system, these muscarinic receptors act to decrease contractility of the atria and ventricles and reduce conduction through the heart
M3 (muscarinic type three) receptors function
found in the eye, other glands and along the vascular endothelium. When the M3 receptors are stimulated by acetylcholine we expect miosis or pupillary constriction as the circular muscle contracts, we expect excretions from the nose, tears from the eyes, defecation and urination.
Metabolism of acetycholine
Acetylcholinesterase hydrolyzes acetylcholine to acetate and choline. Choline can later be taken up by the pre-synapse and used again in synthesis. Two major subtypes of acetylcholinesterase enzymes exist. The first subtype is acetylcholinesterase that is predominate in cholinergic synapses and along the red blood cell membrane. The second subtype, butyrylcholinesterase, is non-neuronally located, and is not essential for life,
Blocking of cholinergic synthesis (drug)
Hemicholinium which halts the reuptake of choline by the choline transporter at the presynapse, ultimately slowing the rate limiting step of choline synthesis.
Blocking of cholinergic storage (drug)
Vesamicol can obstruct acetylcholine uptake into their respective synaptic vesicles.
Blocking of choiinergic release (drug)
Botulinum through prevention of acetylcholine release at all cholinergic neurons. Importantly, when vesicle release is inhibited at the neuromuscular junction, flaccid paralysis occurs.
ALL ganglionic synapses from the spinal cord whether parasympathetic or sympathetic are
nicotinic cholinergic type
ALL parasympathetic target organs are
cholinergic muscarinic type
kidneys prefer what type of stimulation
dopaminergic stimulation, the exception being the occasional β1 receptor that allows for increased renin
