Parasympathomimetics, cholinesterase inhibitors, and ganglionic blockers Flashcards Preview

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Flashcards in Parasympathomimetics, cholinesterase inhibitors, and ganglionic blockers Deck (30)
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NTs used in ANS

-In preganglionic synapses, for both parasympathetic (PsNS) and sympathetic (SNS), Ach is the NT used and it binds to nicotinic receptors (nAchR)
-In the postganglionic nerves for the SNS, norepinephrine is the NT used (adrenergic neurons) on the effector organs
-In the post ganglionic nerves for the PNS, Ach is still the NT and it binds to muscarinic receptors on the effector organs (mAchR). These neurons are cholinergic


Differences/similarities btwn PsNS, SNS, and somatic

-PsNS and SNS both use Ach in the ganglia to bind to nAchR (this includes SNS innervation of adrenals)
-But PsNS uses Ach and mAchR in the postganglionic synapses (onto effector organs), whereas SNS uses norepinephrine (NE) and adrenergic receptors in the postganglionic synapses (effector organs)
-In the adrenals there is no postganglionic synapse. Once stimulated by SNS release of Ach on the nAchR, the adrenals act like the postganglionic cell by releasing epinephrine into the blood
-In somatic NS (motor), there is no ganglia, and the motor neuron releases Ach into the NMJ to bind to nAchR and cause contraction


Sympathetic vs parasympathetic responses

-Sympathetic: dilation of pupil bronchi, inhibition of gastric motility, urination, salivation. Most important: heart rate accelerates, blood vessels constrict
-Para: the opposite of the above. Most important: heart rate decreases, but no effect on blood vessels


Important effects of PsNS 1

-Contraction of ciliary muscle causes lens to convex and focus on up-close vision (accommodation), along w/ miosis (constriction of pupils)
-PsNS action on the heart is all supra ventricular (above the ventricles, in the SA and AV nodes)
-Overall the effect of PsNS on the heart is deceleration of HR and decreased contractility of the atria
-There are NO nerve terminals on the smooth muscle of blood vessels, but there are mAchR. This means that w/ increased PsNS output there will be no effect on the blood pressure, but if you give Ach (or an Ach agonist) it will bind to the mAchR and cause dilation of the vessels (thru release of NO, BP drops)


Important effects of PsNS 2

-Sweat glands do NOT receive PsNS input (only SNS), however the postganglionic SNS nerves on sweat glands use Ach (the exception to NE for postganglionic SNS)
-This means that giving a parasympathomimetic (PSPM) will cause secretion of sweat, even though this is activating a SNS function
-An important effect of increased PsNS is inhibiting the SNS output from postganglionic SNS nerves to the same organ that the PsNS is innervating
-This allows the body to greatly increase the PsNS effect overall, by also reducing the SNS effect when the PsNS is active


Parasympathomimetics (PSPMs)

-Cholinergic agonists that are given as drugs to induce PsNS effects (plus sweat gland release, a SNS effect)
-ALL PSPMs bind to mAchR, but only Ach and Carbachol bind to nAchR
-Types of PSPMs: Ach, carbachol, bethanechol, methacholine, pilocarpine
-These drugs do not only act on organs that receive PsNS input, but act anywhere there is an Ach receptor (such as arterioles/venules)


Types of muscarinic AchRs

-There are 5 types of mAchRs, but we only need to know M2 and M3
-M2: found in CNS, heart, smooth muscle. In heart functions on SA node and AV node to decrease HR, decrease atrium contraction
-M2 inhibits AC and regulate Ca channels
-M3: found in smooth muscles and glands. Cause increased secretion from glands (salivary and lacrimal)
-M3 stimulate PLC


Metabolism of Ach and mimetics

-Ach metabolized into choline and acetate by 2 different nzs: specific cholinesterase and non-specific cholinesterase
-Specific cholinesterase is located in the region of the cholinergic receptor in the synaptic cleft. It can hydrolyze Ach and methacholine (is less specific)
-Non-specific cholinesterase is located in the plasma, and can only hydrolyze Ach (is more specific)
-Thus, bethanechol, carbachol, and pilocarpine are all unable to be hydrolyzed and thus have longer t1/2s than Ach or methacholine (about 4x longer)


Effects of PSPMs on organs

-Methacholine is more specific for the heart/vessels (systemically)
-Bethanechol is more specific for the GI tract and bladder (systemically)
-Pilocarpine and carbachol is used for the eye (surface of eye)
-All have side effects, which can include increased urinary frequency, diarrhea, fall in BP, cardiac arrest, excessive sweating (Ach receptors despite being SNS innervated), wheezing (constricted bronchioles), tearing
-Also causes erection (requires PsNS activation), but not ejactulation (requires SNS activation)


PSPM's effect on heart

-Sinoatrial (SA) node is pacemaker, stimulation leads to increased frequency of atrial/ventricular contractions
-Atrioventricular (AV) node spreads the electrical activity to the ventricles, after a slight delay, causing them to contract
-Chronotropic refers to HR, negative chronotropic effect (such as PSPMs) slows down the HR by acting on the SA node
-Inotropic refers to strength of contraction, negative inotropic effect (such as PSPMs) cause the heart to contract less forcefully
-PSPMs all act supraventricular (in the SA and AV nodes, and the atria), do not effect the ventricles


Baroreceptors and medullary CV centers (MCVC) 1

-Located in carotid sinuses, aortic arch and atria
-When stretched they increase firing, stretching occurs from increase in BP
-Increased firing of the baroreceptors is sensed by the MCVC, which sends out PsNS signals to SA node (thru vagus, X) to decrease firing
-Decreased HR leads to decreased cardiac output (CO), which leads to lower BP


Baroreceptors and medullary CV centers (MCVC) 2

-Simultaneously, the MCVC is decreasing sympathetic output to the heart and blood vessels
-This causes a decreased force of contraction and HR, as well as vasodilation. Together this also contributes to a drop in BP
-These effects then lead to a drop in BP which is sensed by the MCVC which then reverses the outputs to achieve BP homeostasis
-The MCVC/baroreceptor reflex happens instantaneously


Outcome on the CVS when giving Ach

-There is an initial decrease in HR/BP due to the action of Ach
-The MCVC responds accordingly to reduce PsNS output and increase SNS output
-On top of this, Ach is getting broken down immediately
-The effect of the breakdown of the Ach plus the MCVC response leads to an overshoot in HR/BP as the MCVC attempts to bring it back up to normal levels
-The overshoot is sensed by the MCVC and it adjusts its output to bring the HR/BP back to a normal level


Effects of a vasoactive compound

-A compound that is a vasoconstrictor, for example, will increase the BP
-In response to the increase in BP, the MCVC will reduce the HR by increasing PsNS output
-This happens immediately once the vasoconstrictor increased BP, thus the increase in BP is mirrored w/ a decrease in HR
-The two eventually normalize each other and the HR and BP return to a basal level
-For vasoactive compounds, the HR and BP graphs are always exact mirror images of each other (effects are instantaneous)


Cholinesterase inhibitors (CEIs)

-Drugs that block the action of specific (in synapse, both Ach and methacholine) and non-specific (in plasma, only Ach) cholinesterases
-These are only effective in areas that have PsNS innervation, since they require nerve terminals that are releasing Ach to function
-The drugs we need to know are all reversible CEIs
-6 drugs: neostigmine, pyridostigmine, edrophonium, physostigmine, donepezil, galantamine


Cholinesterase inhibitors and crossing the BBB

-Of the 6 drugs (neostigmine, pyridostigmine, edrophonium, physostigmine, donepezil, galantamine), 3 are tertiary and 3 are quaternary amines
-The tertiary amines (physostigmine, donepezil, and galantamine) all can cross the BBB
-The quaternary amines (neostigmine, pyridostigmine, and edrophonium) will not cross the BBB
-Donepezil and galantine are useful in Rxing AD


Action of cholinesterase inhibitors (CEIs)

-Will inhibit cholinesterases that are in the synapses in both PsNS and NMJs
-Even though these two systems may use different Ach receptors, they both still use Ach and thus contain cholinesterases
-They work by inhibiting the nz and increasing Ach's T1/2 in the synapse, thereby activating the receptors more
-The only sympathetic response you will see by using CEIs is in the sweat gland, since this SNS postganglionic nerve uses Ach as its NT


Differences in effects btwn CEIs and PSPMs 1

-Overall they have very similar effects (both lead to increase in AchR binding), but have some differences
-Both CEIs and PSPMs will slow heart rate, however CEIs will not lead to hypotension b/c there is no nerve input on vessels to allow for more Ach binding
-Contrast to this, adding a PSPM will lead to hypotension b/c the PSPM will bind to the mAchRs on the vessels and dilate them
-CEIs effect on ganglia: initially excitatory, then when the receptors are occupied and the cell is depolarized, the effect depression


Differences in effects btwn CEIs and PSPMs 2

-Another difference is induction of skeletal muscle fasciculations (caused by excitation of NMJ by increased Ach+nAchR binding, without direct activation from the motor neuron)
-CEIs will induce skeletal muscle fasciculations b/c they prevent the Ach in the synapse (always a basal level of Ach being released in the NMJ, even w/o motor neuron stimulation) from being broken down
-This higher level of Ach in the synapse leads to transient excitation of the muscle and thus the muscle fasciculates
-PSPMs will not cause fasciculations b/c they do not bind to nAchR, only mAchR (except for carbachol, but that is only used on the eye)


Uses of the CEIs

-Used to generate desired PsNS effects (same as PSPMs), but without the drop in BP that is observed w/ PSPMs
-Examples: Rxing atony of the GI, urinary retention, and glaucoma
-Can also be used for more specific neurological abnormalities, such as AD (donepezil and galantamine), and myasthenia gravis (MG)
-MG is an autoimmune disease where Abs are made against the nAchR in the NMJ. This leads to lower number of functioning nAchR and a diminished response to Ach release (muscle weakness)
-Dx of MG is made by giving edrophonium (due to short t1/2), to allow more Ach to remain in the NMJ
-If the pt has more strength after this, the Dx is MG. Then the pt is started on pyridostigmine b/c of its longer t1/2 and inability to cross BBB


Irreversible CEIs

-Class of drugs called organophosphates, considered irreversible b/c their metabolism is very slow (hundreds of days)
-The slow metabolism leads to massive parasympathetic actions and can lead to death
-Nerve gases (sarin) fall under this category, also isofluorophate and parathion
-Most of them cross the BBB, leading to extreme levels of Ach in the CNS and nausea, coma, seizures, and death can occur
-Organophosphates inhibit cholinesterase by phosphorylating it
-The phospho group can be removed by the drug pralidoximine (PAM)
-The muscarinic receptors can also be protected by atropine


Ganglionic blockers location of action

-Bind to the nAchR in ganglions (both PsNS and SNS), including in the adrenals to prevent the release of epinephrine into the blood
-Ganglionic blocker we need to know: hexamethonium
-They inhibit the action of Ach at these synapses
-The blockers only bind to ganglionic nAchR, and not NMJ nAchR since the NMJ nAchR is slightly different
-The ganglionic nAchR has Ach binding sites 6 carbon atoms apart, where as the skeletal muscle nAchR has Ach binding sites 10 atoms apart
-This difference causes ganglionic blockers to bind specifically to ganglionic nAchRs


Effects of ganglionic blockers 1

-Since ganglionic blockers affect both PsNS and SNS ganglionic synapse, there will be a reduction of both PsNS and SNS output to organs (but not to the same degree)
-Parasympathetic output is diminished more so than sympathetic output, meaning that sympathetic responses from organs will dominate (except in heart and blood vessels)
-This is b/c inhibition of the PsNS leads to diminished inhibition of SNS by the PsNS (disinhibition of the SNS from the PsNS), leading to an overall higher SNS response from most organs (again, except heart and vessels)


Effects of ganglionic blockers 2

-Ganglionic blockers induce SNS responses from organs, since the SNS predominates (except heart and vessels)
-Expansion of pupil (myadris), relaxation of ciliary muscle (far vision)
-Suppression of glands (salivary, lacrimal, sweat). Sweat glands suppressed b/c they use nAchR (same as in ganglion)
-Atony of GI, urinary retention


Ganglionic blockers on cardiovascular and heart

-In blood vessels there are no PsNS neurons, so ganglionic blockers only prevent the sympathetic input to vessels
-This leads to vasodilation and decreased BP
-Lower BP means less venous return (blood pooling in veins) and therefore less end-diastolic volume (EDV- the amount of blood in ventricles before systole)
-Lower EDV leads to lower stroke volume (SV), because the cardiac muscle aren't stretched as much thus causing a smaller force of contraction
-This phenomenon (due to the frank-starling law, which relates increasing EDV to increasing SV) along with reduced sympathetic input to the AV node (decreasing firing rate) and the heart muscles (decreasing contractility) results in lower cardiac output and hypotension


Baroreceptor reflex and ganglionic blockers

-The baroreceptors will detect the fall in BP due to ganglionic blockers (decreased stretch of receptor -> decreased firing to MCVC)
-The MCVC will increase sympathetic output to compensate, but this will be prevented in the ganglia by the ganglionic blockers
-Therefore the reflex is prevented, and if a pt tries to stand up when on ganglionic blockers the blood pooled in legs will not be returned to the heart to be sent to the brain and they may faint due to anoxia


Vasoactive compounds and ganglionic blockers

-Without ganglionic blockers, Rx with a vasoconstrictor will cause a drop in HR as soon as the BP rises to compensate
-W/ ganglionic blockers there is no functioning reflex and the HR will not change when the BP rises
-Without ganglionic blockers, Rx with a vasodilator causes the HR to increase as soon as the BP falls
-W/ a ganglionic blocker the HR will no change as the BP falls


Rx of nicotine vs PSPM vs CEI

-Nicotine Rx: PsNS predominates (more PsNS inhibition of the SNS), except in CVS. Does cause hypertension (increased SNS causes constriction of vessels), does cause fasciculations
-PSPM Rx: PsNS predominates (only binding to para-post mAchR); does not cause hypertension (causes hypotension by binding to mAchR receptors on vessels and dilates them). Does not cause fasciculations
-CEI Rx: PsNS predominates; does not cause hypertension or hypotension, does cause fasciculations


Ach vs nicotine

-They both act as agonists on ganglia, skeletal muscle, and adrenals
-Ach is brief duration, nicotine is prolonged
-Ach is inactivated by cholinesterase, nicotine is not
-The is no depolarization block from Ach, but there is from nicotine at high doses


Hexamethonium vs atropine

-Atropine blocks only muscarinic receptors (decreases PsNS, SNS predominates), whereas hexamethonium blocks only nAchR in ganglia (decreases both, but SNS still dominates)
-These therefore have parasympathetic actions in common (reduces PsNS), but differ in that hexamethonium inhibits the SNS and atropine does not

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