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Pharmacology 6

Pharmacology 6

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Published by: DrFreethink on Jul 04, 2012
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12/27/2012

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PharmacologyLecture 6 Autonomic Pharmacology
1)Describe the anatomical organization of the sympathetic and parasympatheticdivisions of the autonomic nervous system (ANS).
 
Sympathetic division
– sympathetic nerves arise from the thoracic and lumbar divisions(thoracolumbar) of the spinal cord. Preganglionic sympathetic fibers originate fromneurons in the intermediolateral columns of the spinal cord, are carried over the ventralroots to paravertebral and prevertebral ganglia, and synapse with postganglionic fibersin the sympathetic chain (paravertebral) and abdominal organs (prevertebral). Collateralfibers connect preganglionic fibers with ganglion cells for mass discharge
 Adrenal medulla
– Chromaffin cells, ganglion cells that have not differentiated intoneurons, receive innervation from sympathetic preganglionic fibers through the greater splanchnic nerve.
 Parasympathetic division
– parasympathetic nerves arise from cranial nerves (III, VII,IX, and X) and from the sacrum (craniosacral) and synapse with ganglion cells locatedin the effector organ.
 Enteric division
– consists of an intrinsic intramural collection of myenteric andsubmucosal plexuses located in the GI tract and modulated by extrinsic sympatheticand parasympathetic fibers.
2)Describe the sympathetic nervous system response to “fight or flight” situations.
General discharge of the sympathetic nerves and adrenal medulla in response to stressis termed the “fight or flight response.” The following are sympathetic responses:
Pupil – dilation
Heart – acceleration
Most arterioles – constriction
Salivary gland – secretion
GI smooth muscle – relaxation
Bronchial smoothmuscle – relaxation
Spleen capsule -constriction
3)Describe how single innervation of the arterioles by the sympathetic division canlead to both constriction and dilation of these blood vessels.
Arterioles aredistensible tubes filled with a liquid under pressure. Vasoconstriction is achievedthrough sympathetic activation, which causes smooth muscle contraction and vesselnarrowing. Vasodilation occurs when sympathic stimulation ceases. This allows thevessels to dilate passively due to the distending force produced by the blood pressure.
4)List the three major transmitters of the autonomic nervous system.
Acetylcholine,epinephrine, and norepinephrine.
5)List the five steps of neurotransmission.
 
1.Synthesis
of the transmitter chemical.
2.Storage
of transmitter molecules in vesicles transported by microtubules.
3.Release
of transmitter in response to a nerve action potential and diffusion of transmitter from its site of release from the pre-junctional neuron to its
4.Interaction
with the effector membrane on the postjunctional effector cell and
5.Termination
of action of the neurotransmitter by enzymatic degradation, reuptakeinto the terminal, or diffusion away from the site of action.
6)Describe the sites in the ANS where acetylcholine is the neurotransmitter.
Acetylcholine is the neurotransmitter at sympathetic ganglia, parasympathetic ganglia,adrenal medulla, parasympathetic post-ganglionic nerve terminal, and neuromuscular  junction of somatic nerves and skeletal muscle.
 
7)Describe the major mechanism by which acetylcholine is inactivated, by whichnorepinephrine is inactivated.
 
 Acetylcholine’s
actions are terminated rapidly byacetylcholinesterase, which hydrolyzes acetylcholine into acetate and choline. Cholinecan then be transported back to be used in acetylcholine synthesis.
 Norepinephrine’s
actions are terminated by (1) reuptake into the terminal, (2) oxidativedeamination by monamine oxidase in mitochondria, (3) 0-methylation by catechol-0-methyltransferase, and (4) diffusion away from the synapse.
8)Identify the sites in the ANS where neurotransmission is mediated by nicotinic ormuscarinic acetylcholine receptors.Nicotinic
cholinergic receptors are located on: (1) all autonomic sympathetic and parasympathetic ganglia (including the adrenal medulla) and (2) the neuromuscular  junction of somatic nerves and skeletal muscle.
Muscarinic
cholinergic receptors are located on: postganglionic parasympatheticneuroeffector cells.
9)Describe the sites in the ANS where norepinephrine is used as theneurotransmitter.
Norepinephrine is the neurotransmitter for most sympathetic postganglionic neuroeffector junctions. The one exception is innervation othermoregulatory sweat glands, which uses acetylcholine, although the palms still usenorepinephrine (clammy hands when stressed).
10)List the two general types of adrenergic receptors.
Alpha (α) and beta (β). Alphastimulation is usually excitatory (except in the gut). Beta stimulation is usuallyinhibitory (except in the heart). In the GI tract both relax smooth muscle while in theheart beta simulation increases rate and contractility.
11)Describe the origin of epinephrine and its site of release.
 
Origin
: The amino acid tyrosine is hydroxylated by tyrosine hydroylase to formdihydroxyphenylalanine (DOPA) and is then decarboxylated by DOPA decarboxylaseto form dopamine. Dopamine is hydroxylated in vesicles on the β carbon of theethylamine side-chain by dopamine β-hydroxylase to form norepinephrine. In certainareas of the brain and the adrenal medulla, norepinephrine is methylated on the aminegroup by phenylethanolamine-N-methyltransferase to form epinephrine.
Site of release
: Epinephrine is release from the adrenal medulla into the blood stream,think of it like a neurohormone.
12)Describe the sympathetic/parasympathetic neurotransmitters and their receptorsfor increasing or decreasing heart rate.
 
Sympathetic (thoracolumbar)
Acetylcholine (preganglionic) Norepinephrine (postganglionic) Nicotinic cholinergic receptor Beta-adrenergic
1
) receptor ↑HR and contractilityresulting in increasedcardiac output
Parasympathetic (craniosacral)
Acetylcholine (vagal preganglionic)Acetylcholine (postganglionic in heart) Nicotinic cholinergic receptor Muscarinic (AV and SA nodes)↓HR and contractilityresulting in ↓CO
13)Describe the effects of sympathetic/parasympathetic activation on pupil size andlens accommodation.
 
Sympathetic (Dark)
Acetylcholine (preganglionic) Norepinephrine (postganglionic) Nicotinic cholinergicAlpha-adrenergic
1
)Pupil dilation(mydriasis) – dialator  pupillae muscle
Parasympathetic (Light)
Acetylcholine (preganglionic)Acetylcholine (postganglionic in eye) Nicotinic cholinergicMuscarinic (constrictor muscle)Pupil contraction(miosis) – constrictor  papillae muscle
 
14)Describe the mechanisms by which adrenergic agonists and muscarinicantagonists both produce mydriasis.
Adrenergic agonists stimulate the alpha-adrenergic receptors (α
1
), which normally occurs due to norepinephrine released fromthe postganglionic fibers to the dilator pupillae muscle, resulting in mydriasis.Muscarinic antagonists prevent parasympathetic stimulation of the constrictor papillaemuscle by acetylcholine causing it to relax, which results in mydriasis.
15)Describe what is meant by denervation supersensitivity.
When the nervous supplyof a muscle or gland is interrupted, the effector organ slowly becomes increasinglysensitive to the neurotransmitter of which it is deprived. This occurs because of upregulation of receptors after one to two weeks.
16)List the common side effects seen with the use of cholinergic antagonists.
 
 Muscarinic receptor antagonists
: dry mouth, constipation, decreased sweating,mydriasis (dilation of pupil), urinary retention (especially in elderly males with benign prostatic hypertrophy), tachycardia, decreased lacrimation, precipitation of glaucoma,and decreased respiratory secretions (increased susceptibility to respiratory infections.
 Nicotinic receptor antagonists
(sympathetic and parasympathetic ganglionic blockers):constellation of severe side effects – constipation (blocking enteric ganglia), atony of the bladder, cycloplegia, decreased sweating, postural hypotension, and tachycardia(SA node dominated by parasympathetics).
17)Contrast the therapeutic advantage of pilocarpine to acetylcholine.
 
 Pilocarpine
exhibits primarily muscarinic receptor agonist actions and it is notdegraded by cholinesterases thus it has a 2-3 hour duration. It can be given orally.
 Acetylcholine
however, is a non-selective agonist of both muscarinic and nicotinicreceptors and its duration is very brief because it is rapidly hydrolyzed by plasmacholinesterases. It cannot be given orally.
18)Describe the differences between a direct and indirect acting cholinergic drug.
 Direct acting 
agonists bind to the cholinergic receptor and mimic the effects of thenatural receptor ligand acetylcholine.
 Indirect acting 
agonists inhibit the destruction of acetylcholine by acetylcholinesterase,thereby increasing the synaptic concentration of acetylcholine which then acts on thecholinergic receptor.
19)Identify the major advantage for using quaternary cholinesterase inhibitors.
Quaternary cholinesterase inhibitors, neostigmine and edrophonium, do notsignificantly cross the blood-brain barrier, and therefore, they are useful for treating peripheral disorders like intestinal and bladder atony and for the management of myasthenia gravis.
20)Describe the drug of choice for reactivating cholinesterase shortly afterorganophosphate poisoning.
The treatment of choice for severe intoxication withcentrally acting cholinesterase inhibitors is atropine, given in large doses to combat thecentral manifestations (confusion, ataxia, convulsions, coma, and respiratory paralysis)and the peripheral signs (bronchial secretions, hypotension, and involuntary twitchingleading to paralysis) resulting from overstimulation of muscarinic receptors.
 Atropine
isa muscarinic receptor antagonist, a tertiary amine capable of penetrating into the CNSand blocking all subtypes of muscarinic receptors.
21)Describe the major symptoms of a cholinergic crisis.
The common signs of “cholinergic crisis” are salivation, lacrimation, urination, defecation, emesis (“SLUDE”syndrome).
22)Describe the therapeutic uses of muscarinic agonists.
 

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