Cholinomimetic drugs week 1

Question 1

cholinomimetic drugs

cholinolytic drugs

Answer 1

The cholinomimetic drugs mimic the actions of ACh as opposed to cholinolytic drugs (cholinergic antagonists), which antagonize the effects of ACh.

Question 2

What are the primary clinical uses of cholinomimetics?

Answer 2

The cholinomimetics are primarily used in the management of glaucoma, GI and bladder dysfunction, treatment of Myasthenia Gravis (MG), treatment of mild Alzheimer’s disease (AD) and in surgery to produce muscle relaxation. They have important toxicological implications in various types of poisonings.

Question 3

At what receptors do non specific cholinomimetics act?

What is the structure of all nonspecific cholinomimetics? What implication does their structure have on the way they are adminstered? Their distribution in the body?

Answer 3

Nonspecific cholinomimetics act at all cholinergic receptors because they mimic the action of ACh due to their structural similarity to ACh. All are quaternary amines like ACh and esters. As quaternary amines, they will not cross lipid barriers like the blood brain barrier (BBB) or would not be absorbed well from the intestine.

Question 4

What enzyme(s) biotransform nonspecific cholinomimetics?

Explain their affinites for these enzymes and how this relates to their efficacy.

Answer 4

Have varying affinities for AChE. Where ACh has effects for only 30 seconds, a drug like bethanechol has less affinity for AChE and thus has a longer t1/2. These drugs should have low affinities for AChE, since if they had high affinities, they would also have AChE inhibitory effects. Butyrylcholinesterase (also called pseudo-cholinesterase and located in plasma) will also break these drugs down.

Question 5

Name 3 nonspecific cholinomimetic drugs.

Answer 5

bethanecol

carbechol

methalcholine

Question 6

What receptors does bethanecol act on?

What are the effects of this drug?

What are the clinical uses of bethanecol?

What are the toxicities/side effects?

Answer 6

Bethanechol, the prototypical:

a. Is a full agonist at M1- M3, with little effect on N.
b. Produces effects typical of muscarinic drugs (i.e., increased secretions, smooth muscle contraction, and reduced heart rate.
c. Primarily used post-op and in neurogenic illeus and urinary retention to stimulate bowel movements and urination.

Caution: Cannot be used in obstructions as this would cause distention that could lead to rupture.

Caution: Bonchospasm can be exacerbated especially in asthmatics.

Activates bowel and bladder smooth muscle. Bethany, call (bethanechol) me, if you want to activate your bowels and bladder.

Question 7

What receptors does carbecol act on?

What are the effects of this drug?

What are the clinical uses of carbecol?

What are the toxicities/side effects?

Answer 7

Carbechol acts on M and N receptors. It is used to treat glaucoma (increase fluid drainage of aqueous humor through trabecular meshwork). Also used for pupillary contraction and relief of intraocular pressure.

Lippincott: It is locally instilled into the eye and causes miosis and a spasm of accommodation in which the ciliary muscle of the eye remains in a constant state of contraction. No systemic toxicities/side effects bc adminstered locally

Question 8

Name two specific muscarinic direct acting agonists.

What chemical class are they in? How are their effects terminated?

Answer 8

muscarine

pilocarpine

Both are alkaloids and are excreted for termination.

Question 9

What is the chemical structure of muscarine?

What effect does its chemical structure have on the way it is adminstered? Its distribution?

What receptors does it act on?

What are the effects of muscarine?

What are the toxicities?

Answer 9

Muscarine is a quaternary amine and does not readily cross membranes (or enter brain) although sufficient amounts enter to produce toxic effects after ingestion of large quantities of certain mushrooms.

Muscarine has full action at all M receptors with no N activity.

Its effects are those typical of muscarinic drugs (i.e., increased secretions, smooth muscle contraction, and reduced heart rate. (SLUDGEM effect: salivation, lacrimation, urination, defecation, GI upset, emesis, miosis)

Can precipitate bronchospasm, especially in asthmatics.

Question 10

Explain the ability of pilocarpine to distribute throughout the body.

What receptors does it act on?

What are the effects of pilocarpine?

What are the clinical uses?

What are the toxicities?

Answer 10

Pilocarpine is tertiary and readily crosses membranes. Both pilocarpine and muscarine are excreted to terminate action.

a. Is a full agonist at M1- M3, with little effect on N.
b. Its effects are those typical of muscarinic drugs (i.e., increased secretions, smooth muscle contraction, and reduced heart rate
c. Potent stimulator of sweat, tears, and saliva.Pilocarpine is primarily used in glaucoma as an eye drop. Contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed angle glaucoma), resistant to AChE. “You cry, drool, and sweat on your pilow”
d. Can precipitate bronchospasm, especially in asthmatics. Can enter the brain and cause CNS disturbacnes. Stimulates profuse sweating and salivation.

Question 11

Name direct acting nicotinic agonists (nicotinic cholinomimetics).

What is their chemical structure? What effect does this have on their distribution and mode of excretion?

Answer 11

The nicotinic, direct acting agonists include nicotine (after which the receptor was named) and lobeline. Both are tertiary amines, readily cross membranes, and are primarily excreted. Nicotine is adequately soluble enough in membranes to allow it to cross subcutaneously and it is thereby delivered via patches for the treatment of cigarette addiction.

Question 12

What receptors do nicotine and lobeline act on?

What are their effects?

What are the clinical uses?

What are the toxicities/side effects?

What is the relationship btwn nicotine and PD?

Answer 12

They are both full agonists at Nn and Nm receptors.

b. They both activate SANS and PANS (Nn at ganglia) and activate striated muscle (Nm).
c. Nicotine is widely used in smoking cessation and being explored for treatment of Attention Deficit/Hyperactivity Disorder (ADHD).
d. Toxic effects include increased GI activity with nausea, vomiting, and diarrhea; increased BP and potential for seizures.

Nicotine reduces the risk of Parkinson’s disease (PD).

Question 13

Explain the relationship btwn tobacco smoke and monoamine oxidase inhibitors (MAOIs). What NTs are affected by this? How does this influence nicotine addiction?

What NT does nicotine directs increase the release of? Via what mechanism? What are NANC receptors?

Answer 13

Tobacco smoke produces several Monoamine oxidase inhibitors (MAOI) and this action, increases DA as well as NE and 5HT, which contribute to smoking’s dependence and euphoric effects given that DA is the primary mediator of initial addiction (DA acts on pleasure center-ventral striatum aka nucleus accumbens).

Nicotine also increases DA in the CNS through its activation of α4β2 nicotinic Nn receptors located presynaptically on DA terminals.

Drugs acting through cholinergic receptors act directly on the receptor itself, act at presynaptic autoreceptors, or through heteroreceptors on other nerve terminals, non-adrenergic/non-cholinergic heteroreceptors (so called NANC receptors). The action of nicotine or lobeline on DA terminals would be an example of a NANC receptor action.

Question 14

What receptors does varenicline act on?

Where are these receptors located?

What are the effects of varenicline?

What is the clinical use of varenicline?

What are the toxicities?

Answer 14

Varenicline (Chantix) is a partial agonist at α4β2 nicotinic Nn receptors, which are preferentially found in the limbic system of the CNS and associated with nicotine cravings. α4β2 nicotinic Nn receptors are heteroreceptors located presynaptically on DA terminals (NANC receptor) and varenicline thereby reduces DA release and the “addictive supporting actions of DA.”

1. As a partial agonist it “feeds” the addiction somewhat, while preventing full nicotinic effects of the cigarette if smoked.
2. Principle is that during withdrawal, it provides some mild sensation of continued nicotine intake making it easier to quit.

Lippincott: Pts should be monitored for suicidal thorughts, vivid nightmares, and mood changes.

Question 15

What is the function of indirect acting cholinomimetics?

Where are their effects observed?

What are the toxicities/side effects?

Answer 15

Indirect-acting cholinomimetics: As a class, these drugs act primarily by inhibiting AChE and are thus AChEIs. These drugs also have variable effects on butyrylcholinesterase. Because of this indirect action, these drugs potentiate all the effects of ACh in the periphery, and for those that enter the CNS, in the brain as well. Because it increases ACh body wide, AChEIs also produce SANS effects by inhibiting catabolism of ACh at the preganglionic synapse.

have muscarinic and nicotinic effects, SLUDGEM predominates

Question 16

Explain the type of binding that occurs btwn ACh and AChE.

Describe the process of ACh breakdown by AChE.

What 3 chemical classes do AChEI’s fall under?

Answer 16

AChE has two binding sites that become important in understanding the MOA of these drugs, the duration of their effects, and the species selectivity of their actions. ACh binds reversibly to the active site of the AChE in a two-step process. Electrostatic binding and hydrolysis followed by hydration of the covalent acetyl-enzyme complex re-constituting the enzyme and yielding choline and acetate. Chemically, the inhibitors fall into three classes (alcohols, carbamates, and organophosphates) all of which interfere with this two-step process. They predominantly differ in their binding duration.

Question 17

Explain the mechanism via which alcohol AChEIs prevent AChE action.

Give an example of an alcohol AChEI and explain how it works. What is the structure of this drug? Explain its distribution in the body.

Answer 17

Alcohols (e.g., edrophonium) bind electrostatically and by hydrogen bonding similar to ACh and are rapidly reversible. Since they bind to the AChE, they prevent ACh from binding to AChE and increase ACh residence time in the synapse. While edrophonium is bound to AChE, ACh cannot be hydrolyzed. There are no covalent bonds formed and the AChEI comes off the enzyme in several minutes. It is a quaternary amine and does not cross the blood brain barrier (BBB).

Question 18

What are the clinical uses of edrophonium? What is the effect of edrophonium?

Answer 18

Edrophonium is used to diagnose myasthenia gravis (Tensilon test). It increases the amount of endogenous ACh.

Question 19

Name two carbamate AChEIs. Explain the mechanism of action of these drugs.

Answer 19

Carbamates (e.g., neostigmine and physostigmine) are processed like ACh, but the second carbamoylation step is slowly hydrated yielding longer occupancy and therefore blockade for hours.

Question 20

What are the structures of neostigmine and physostigmine? Describe how the structures determine their distribution.

What are the clinical uses of these drugs?

What are the toxicities?

Answer 20

Neostigmine is quaternary and does not cross the BBB whereas physostigmine is tertiary and does enter brain.

Neo CNS: No CNS penetration (neostigmine)

Neostigmine acts to increase endogenous ACh. It is used for postop and neurogenic ileus and urinary retention, reversal of NMJ blockade. Toxicites: SLUDGEM

Physostigmine is used for anticholinergic toxicity (atropine)—> crosses BBB. Increases endogenous ACh. Physotigmine “phyxes” atropine overdose. The effects of physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia and a fall in cardiac output may also occur. Inhibition of acetylcholinesterase at the skeletal neuromuscular junction causes the accumulation of acetylcholine and, ultimately, results in paralysis of skeletal muscle. However, these effects are rarely seen with therapeutic doses.

Question 21

What is the mechanism of action of organophosphate AChEIs?

Name 3 organophosphate AChEIs.

Answer 21

Organophosphates (e.g., echothiophate, parathion and malathion) along with the nerve gasses (e.g., sarin, soman and VX) phosphorylate the esteric site of AChE which ages over time (10 minutes for soman and 48 hours for VX). These drugs are therefore considered irreversible binders of AChE.

Question 22

What is the function of pralidoxime?

Answer 22

Organophosphates (e.g., echothiophate, parathion and malathion) along with the nerve gasses (e.g., sarin, soman and VX) phosphorylate the esteric site of AChE which ages over time (10 minutes for soman and 48 hours for VX). These drugs are therefore considered irreversible binders of AChE. During the aging process, a drug like pralidoxime can bind to the esteric site and regenerate it. Because the AChE can be rescued, it is best to describe their actions as pseudo-irreversible. Once the esteric site ages, however, they are irreversible.

Question 23

What are organophosphates widely used for? Why?

Explain the toxic effects these drugs (when used as in question above) can have and in what organisms.

Answer 23

The organophosphates are widely used as insecticides with the exception of echothiophate (which is quaternary), because they are absorbed rapidly and distributed widely, including to the CNS. They are moderately safe around humans because they are, by and large, protoxins that must be activated to toxic intermediates. This occurs in both insects and humans, but most vertebrates (including humans) and birds rapidly inactivate these intermediates producing reasonable selectivity toward insects. Malathion is an exception and is not inactivated by fish however, and insecticide runoff into water can kill fish.

Question 24

What are nootropics? What is their target? How do they interact with their target?

What is their function?

What is the clincal application of these drugs?

Answer 24

Although there is one gene that encodes AChE, alternative splicing can generate numerous forms of the enzyme with G1 and G4 being most common in brain. Selectivity for these forms can yield greater CNS/PNS selectivity and associated reductions in peripheral side effects. The currently available Nootropics are G1 and G4 preferring. Nootropics are drugs, supplements, nutraceuticals, or functional foods that purportedly improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration.

1. Nootropic drugs are used to enhance cognition and these drugs are used in the treatment of Alzheimer’s disease (AD). The degenerative changes in AD involve (among other changes) loss of ACh and administering AChEIs that prefer G1 and G4 are widely used. As a class, these drugs are all reversible inhibitors with varying half-lives that have only mild to moderate nootropic effects. They are used in the early phases of disease treatment.

Question 25

Name 3 nootropic drugs. (generic and brand name)

Which is most commonly used for the treatment of AD?

What are the side effects of these drugs?

Answer 25

Donazepil (aricept) most commonly used

Rivastigmine (Excelon)

Galantamine (Reminyl)

Nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramps

Question 26

Describe the type of binding btwn AChE and donazepil (aricept).

What is the half life? What does this mean for dosing?

What is the relative bioavailability?

How is donzepil (aricept) eliminated? How does its route of elimination affect its potential for toxicity?

Answer 26

Donepezil (Aricept; Most widely used)

1) Non-competitive, reversible inhibitor
2) t1/2 = 60 hours, producing once a day dosing
3) Typical peripheral side effects with somewhat greater selectivity for CNS AChE (sleep disturbances)
4) High oral bioavailability with some first pass metabolism
5) Most of administered dose is eliminated renally thus reducing the potential for drug interactions. Renal impairment can lead to significant accumulation. Drugs that are cleared predominantly via the renal route are always preferred and generally considered safer drugs. In the absence of biotransformation in the liver and the need for CYP or non-CYP enzymes, there is a significantly reduced risk for drug interaction or drug-disease interaction (liver disease).

Question 27

Describe the binding btwn rivastigmine (Excelon) and AChE.

Answer 27

Rivastigmine (Excelon)

1) Pseudo-irreversible competitive inhibitor of AChE

at active site similar to physostigmine although with

a significantly longer duration of action.

Question 28

Describe the binding btwn galantamine (Reminyl) and AChE.

What is the approximate half life? How does this affect dosing?

How is galantamine eliminated?

Beside AChE, what else does galantamine bind to? What is the effect of this interaction?

Answer 28

Galantamine (Reminyl)

1) Reversible, low potency agent with a t1/2 of 5-6 hours requiring multiple dosing (now available as a patch).
2) Extensively metabolized
3) Also acts as a non-competitive nicotinic (Nn) agonist.

a) As a nicotinic agonist, it can activate post-
synaptic receptors in brain, which has been shown to have some efficacy against AD. (Nicotine patches have been used, but no significant effects seen).

Question 29

Memantine (Namenda)

What is the mechanism of action? How does it bind to its target?

What is the clinical use?

What are the side effects?

Answer 29

Memantine (Namenda) is now used in AD management after the Nootropics are no longer effective (generally moderate to severe AD (Stages II and III)). It is a mild NMDA indirect-acting Glu antagonist. A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer’s disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. By binding to the NMDA receptor with a higher affinity than Mg++ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the presynaptic neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer’s disease. Memantine is, in general, well-tolerated. Common adverse drug reactions (≥1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido.

Question 30

What are the side effects of muscarinic agonists?

Answer 30

SLUDGEM: Salivation, lacrimation, urination, defecation, GI upset, emesis and miosis

Question 31

What receptor is mostly responsible for salivation?

What are the functions of vasoactive intestinal peptide (VIP)?

Answer 31

Salivation: M3 > M1 which causes contraction of smooth muscle of the glands and secretion of watery saliva.

1. Vasoactive intestinal peptide (VIP) is co-localized in PANS terminals and released at higher frequencies of stimulation. When released, this co-localized large molecule neurotransmitter reduces vascular resistance increasing blood flow to the gland and thereby increases saliva production. Acting through its receptors it also enhances the post-synaptic signaling of ACh on Acinar cells—>GI secretions.

Question 32

Sjogren syndrome

definition, symtoms

Answer 32

Sjogrens syndrome: lymphocytic infiltration of exocrine glands, especially lacrimal and salivary

classic triad: Xerophthalmia (abnormal dryness of the conjunctiva and cornea of the eye, with inflammation and ridge formation), xerostomia (dry mouth), arthritis

parotid enlargement, increased risk of B-cell lymphoma, dental carries

Question 33

What nervous systems play a role in urination (micturition)?

What nerves mediate the urination relfex?

Explain PANS and SANS control of urination.

State what PANS and SANS receptors are involved in control of urination.

What are the side effects of cholinomimetics on the bladder?

Answer 33

Physiologically, micturition involves reflexive coordination between the central, autonomic and somatic nervous systems. Brain centers that regulate urination include the pontine micturition center, periaqueductal gray, and the cerebral cortex. The urge to urinate occurs generally when the bladder is filled with 300-400 ccs. Pelvic sensory nerves mediate the reflex, which involves voluntary control of the external sphincter, which also signals PANS reflexive activation to cause contraction of the detrussor, primarily by a M3 mediated action. M2 receptors are most prevalent in the detrusor, but likely function presynaptically to inhibit release of NE from SANS terminals, which through beta receptors, induces relaxation. The trigone is normally contracted and spontaneously active. This activity helps maintain the patency of the ureteral openings while causing closure of the internal urethral sphincter (which is not really a sphincter but behaves as one with parallel smooth muscle fibers). During micturition, this activity is relaxed closing the ureteral openings and opening the internal urethral sphincter. There is a complex interplay between PANS and SANS in regulating bladder function that will be covered later. Thus, cholinomimetics will cause urinary urgency and produce adequate contraction of the detrusor to overcome voluntary control of the external sphincter via a M3 mediation contraction. (Drugs used to manage urinary incontinence will be discussed later).

Question 34

What PANS receptors are involved in defecation?

What nerves control defecation?

What is the consequence of muscarinic agonists on defecation?

Answer 34

Defecation: The defecation cycle is very similar to the urination cycle with ANS and voluntary control. Peristaltic contraction waves in the rectum are under PANS control by sacral efferents working through muscarinic M3 receptors and enhance rectal filling creating the sense of fullness and the need to defecate. If intense enough, external sphincter control can be overcome. Often the consequence of muscarinic agonism is watery diarrhea (dysmotility diarrhea). This results from a markedly reduced transit time due to increased peristalsis associated with inadequate absorption and a watery diarrhea. The muscarinic agonists will also increase secretions, which contributes as well.

Question 35

What areas of the brain are involved in controlling emesis?

Explain the mechanism and NTs/receptors involved in the triggering of vomiting.

Answer 35

Emesis: The emesis induced by cholinergic stimulation is a consequence of central pathways. Specific brainstem areas which mediate motion-induced emesis include the area postrema (AP) which is also referred to as the chemoreceptor trigger zone (CTZ), vagal nuclear complex (VNC), reticular formation (RF) at the site of the vomiting center, and the vestibular complex (VC).

1. The CTZ itself has muscarinic receptors, but is predominated by DA and 5HT receptors. Stimulation of these cholinergic receptors by direct-acting agonists can induce vomiting, but high dose, extended exposure is needed.
2. The CTZ and vestibular complex project to the medullary vomiting center, which is rich in cholinergic fibers. Both direct and indirect acting cholinergic agonists that enter brain (i.e., are lipid soluble) increase this afferent activity which stimulates the CTZ which then projects to the vomiting center. Stimulation leads to a feeling of motion sickness that is experienced as nausea and eventually vomiting. Cholinergic drugs would induce vomiting if there was differential stimulation of the vestibular apparatus as this structure activates the vomiting center when there is a left-right mismatch, which frequently occurs in motion sickness. Based on this mechanism, motion sickness is effectively treated with an antimuscarinic drug (i.e., scopolamine patches (see next chapter)).

Question 36

Explain the effects of ACh action on muscarinic receptors in the eye. State what receptors are involved and their functions.

Answer 36

Miosis MIOSIS ACCOMODATION and GLAUCOMA (MAG)

1. Application of ACh acting on M3 receptors in the eye causes muscarinic-induced contraction of the sphincter and ciliary muscle producing miosis and accommodation (cycloplegia or paralysis of accommodation), respectively. These contractions also pull on the trabecular meshwork draining the anterior chamber and thereby reduce intraocular pressure. Again, these responses involve M3 and M2 receptors with M3 mediating the smooth muscle contraction and M2 inhibiting the counteracting SANS effects by reducing NE release.
   a. pilocarpine (direct M1-M3 agonist) is widely used in the management of glaucoma

Question 37

What are the effects of PANS activity on the CV system? What receptors mediate these responses?

Answer 37

Cardiac: Although not part of the SLUDGEM acronym, the effects of PANS activity on the cardiovascular system involve vasodilatation mediated by ACh-
induced release of NO (M3 effect) producing transient reductions in blood pressure together with negative chronotropic, inotropic, and dromotropic effects. Many of these effects will be masked by reflexive responses from the baroreceptor, which will be covered in detail in the adrenergic chapters.

1. The vascular bed effects are normally mediated by M3 receptors working indirectly through NO. Although there is no direct PANS innervation, circulating ACh, not affected by butyrylcholinesterase, or by direct-acting agents will produce dilatation leading to transient reductions in BP, which will be compensated for by increased baroreceptor reflex vasoconstriction.
   a. In vascular disease (e.g., atherosclerosis), M3 mediated NO production is markedly reduced and the overall effect is to produce vasoconstriction.
   b. In coronary vessels, the same principle is at work, although the effect on vascular tone is less pronounced.
2. ACh, acting through M2 receptors, increases potassium currents in the sinoatrial (SA) and atrioventricular (AV) nodes as well as in atrial (primarily) and, to a lesser extent, ventricular cardiac muscle. ACh reduces the slow inward Calcium current and also reduces the hyperpolarization-activated current. These effects result in:
   a. a negative chronotropic effect due to reduced SA node activation
   b. decreased conduction velocity (negative dromotropy) through the AV node.
   c. negative inotropic effect in the atria
   d. negative inotropic, albeit mild, in the ventricles.

Question 38

What cholinergic receptors are present in respiratory system? What are the effects of ACh acting on these receptors?

What cholinergic receptors are present on eccrine sweat glands? What are the effects of ACh acting on these receptors?

Answer 38

Respiratory system: M3-mediated effects produce smooth muscle contraction in the bronchial tree. M3-mediated effects also induce secretion of mucosal cells. Combined, these effects can have devastating effects in asthmatic patients.

Sweat glands: Eccrine (Merocrine) glands are stimulated by M3 receptors to secrete sweat reducing body temperature by evaporative cooling. These are separate from apocrine glands that secrete a more viscous sweat around hair cells.

Question 39

Why are indirect AChEIs (indirect ACh agonists) used instead of direct acting drugs in the treatment of myasthenia gravis?

Answer 39

Indirect agonists are used instead of direct acting drugs so as to potentiate the effects of normally released ACh creating more normal muscle control.

Question 40

What is a Tensilon Test? What is it used for? Explain how this test works.

Answer 40

Pyridostigmine or neostigmine and ambenonium are used. Indirect agonists are used instead of direct acting drugs so as to potentiate the effects of normally released ACh creating more normal muscle control.

a. Patients managed with pyridostigmine, (a quaternary compound that does not cross the BBB) can exhibit MG signs due to too little or too much drug. Too little drug symptoms are obvious. However, too much drug produces muscle weakness caused by excessive Nm stimulation producing depolarization blockade.
b. Edrophonium (Tensilon and referred to commonly as the Tensilon Test) is a very short acting quaternary AChEI and is diagnostic. If administration improves weakness, the pyridostigmine dose is too low. If weakness increases, the pyridostigmine dose is too high.

Question 41

What are other clinical uses of AChEIs outside of myasthenia gravis?

Answer 41

AChEIs can be used to produce muscle paralysis secondary to depolarization blockade in surgery although direct-acting Nm agonists like succinylcholine are widely used as well. The AChEIs are also used to reverse curare-like drug NMJ blockade in surgery. (curare: reversible Nm inhibitor). The curare-like drugs are used in surgery to produce complete muscle relaxation, but they often reverse slowly. To facilitate patient recovery, AChEIs are used to re-instate normal muscle tone.

Question 42

T or F: AChEIs have a greater effect on the increase in nicotinic tone than muscarinic tone.

What are the effects of AChEIs on the CV system?

Answer 42

1. False. SLUDGEM-like effects are generally observed in response to AChEIs due to the muscarinic effects, and although AChEIs will also increase nicotinic tone because of their actions at preganglionic sites, the SLUDEGEM effects predominate.
2. CV effects are similar to muscarinic effects with a notable exception. Generally, AChEIs produce increased BP due to vasoconstriction. This is a consequence of the fact that SANS is the predominant tone in vascular beds and there is no direct innervation of vascular beds by PANS fibers. The preganglionic sympathetic effects of AChEIs, will increase ACh in the ganglia which will activate Nn receptors to increase SANS tone and produce vasoconstriction. This preganglionic effect will also cause the release of Epi producing central CNS agitation associated with EPIs anxiogenic effects (mediated by action on peripheral receptors that then transmit signal into the brain).

Question 43

What drugs are commonly used in the managment of the following conditions:

post-op urinary retention

post-op neurogenic ileus

Answer 43

Management of Post-operative Urinary retention: A single dose of bethanechol is commonly used in cases where there is NO OBSTRUCTION. Other drugs including alpha blockers are also used as are sedative hypnotics such as midazolam.

Management of Post-operative (neurogenic) ileus: Common problem associated with anesthesia and abdominal surgery. Causes are multi-factorial involving effects on the ANS, inflammation, and especially the use of opioid drugs, the constipating effects of which are legend. Neostigmine has been used successfully although other treatments are also used.