Cholinergic Antagonists week 1 Flashcards
What is the prototypical parasympatholytic drug?
What are these drugs used for clinically?
Cholinergic antagonists are used in variety of clinical situations to treat autonomic dysfunction resulting from disease states. They are also widely used in anesthesia to produce NMJ blockade (curare-like drugs), management of asthma and COPD, GI disorders, opthalmic uses, and in treating overactive bladder. With the exception of NMJ blockade of NM receptors, most of these drugs are used to reduce muscarinic tone and are therefore often referred to as parasympatholytic drugs. Thus, they block one or more of the 5 M receptors, although they are generally non-specific in this regard. Atropine is the prototypical drug.
What receptors does atropine bind to? How does it bind to these receptors?
What are the clinical uses of atropine?
Where is atropine found in nature?
MOA of atropine is as a surmountable antagonist (can be reversed by increasing ACh, usually with an AChEI) at all five M receptors (no N activity). Atropine traps the ACh M receptor in the inactive state blocking binding and signal transduction at the site.
decrease airway secretions in surgery (leads to urinary retention and GI hypomotility), bradycardia, opthalmic applications
Atropine is found in the plant Atropa belladonna (Deadly nightshade) and Jimson weed. Consumption of these plants can lead to toxicity. The toxic profile helps in determining the general actions of these drugs:
What receptors to scopolamine and iptratropium act on?
What are their effects?
What are their clincal uses?
Explain their capacity to distribute throughout the body.
Scopolamine M1-M5 >>Nn
Ipratropium: M1-M5 >> Nn
Both scopalamine and ipratropium trap the ACh M receptor in the inactive state blocking binding and signal transduction at the site.
Scopalamine: extremely lipid soluble (can cross BBB) and can be absorbed across the skin. Scopolamine patches are widely used to treat motion sickness as the vestibular system uses a number of cholinergic fibers in its projections. Reduces ariway secretions in surgery
Ipratropium: Ipratropium is aerosolized and inhaled to treat asthma and especially COPD. By blocking M3 receptors in the bronchial tree, ipratropium will reduce mucous production and increase airway caliber. COPD treatment is often accompanied with a beta-2 agonist (Albuterol family). Ipratropium is a quaternary compound and does not cross membranes well so aerosolized drug does not leave the bronchiole tree producing few systemic effects.
What receptors do oxybutynin and tolterodine (detrol) act on?
What are their clinical uses?
What are their side effects?
Oxybutynin and to a greater degree tolterodine (Detrol) are M3 preferring antagonists that are used in the management of hyperactive bladder. Other drugs in this class include darifenacin and solifenacin as well as fesoterodine. (These will be discussed briefly here as antagonists. They will be covered in greater detail in the Urogenital Pharmacology Lecture).
Urinary disorders are being widely treated with antimuscarinic drugs in this class. This is particularly true of the newer M3 preferring tolterodine (Detrol) darifenacin, solifenacin and fesoterodine. Oxybutynin is generic and very inexpensive and still effective although its half-life requires more frequent dosing. The new drugs are often available in sustained release formulations.
Remember that M3 receptors are responsible for bladder contraction during micturition.
Side effects would be reduced GI motility (constipation) and dry mouth.
When are muscarinic antagonists contraindicated?
What are the toxicities of muscarinic antagonists?
Contraindications relate to muscarinic antagonism. These drugs are contraindicated in patients with glaucoma, obstructive disorders of the GI and urinary systems, and intestinal atony. Also contraindicated in pts with dementia (see below)
Hot as a Hare, Blind as a Stone, Mad as a Hatter, and Dry to the Bone
There are other mnemonics, but I like this one.
a. Hot as a hare refers to the inability to sweat producing warm-hot, dry skin. The increase in skin temperature is due to lack of evaporative cooling (eccrine glands) and often times motor excitement (CNS effects of anticholinergic drugs) that generates heat. Recall that ACh is released from SANS fibers regulating sweat glands (the major exception), so atropine would block this effect.
b. Blind as a stone refers to the absence of accommodation, which is a muscarinic mediated response. M3 receptors induce contraction of the ciliary muscle allowing for accommdation for close vision. B2 receptors induce relaxation of the ciliary muscle for far vision (seee attached). Atropine and scopalamine eye drops block relax the ciliary muscle leading to cycloplegia and paralysis of accommodation
c. Mad as a hatter refers to the CNS toxidrome of anticholinergic blockade. This leads to delusions with hallucinations along with significant confusion. Since memory and cognitive function depend, in part, upon ACh in the brain, these systems are affected. These drugs are contraindicated in patients with dementia and are often problematic in elderly patients.
d. Dry to the bone refers to no bowel sounds, no spit, no tears and no sweat.
Explain the use of muscarinic antagonists in mushroom poisoning, GI stasis, and heart disease.
Mushroom poisoning treatment. Recall that muscarine is derived from mushrooms and many other mushrooms produce cholinergic toxicity that is reversed by the use of anticholinergics. Similarly, insecticide exposure can produce cholinomimetic effects that would be reduced with these drugs (usually atropine).
GI stasis is a side effect of these drugs, although recall that PANS only serves to modulate the reflexive activity of the ENS. With the advent of other drugs (opioids) and the fact that atropine is only partially effective at reducing GI activity, use of these drugs to reduce a hyperactive GI tract (diarrhea) are uncommon.
Although antimuscarinic drugs would reverse the predominant PANS tone on the heart, these drugs are not widely used in the management of heart disease.
What is the clincal use of NMJ blockers?
What are the two classes of NMJ blockers?
Neuromuscular Junction (NMJ) blockers: This is an important class of drugs that is widely used in surgery to produce significant muscle relaxation as part of anesthetic plane. The principle here is that most anesthetics are poor muscle relaxers at normally administered doses. In order to get full muscle relaxation, the anesthetic dose would need to be increased. Given that most anesthetics have very low TIs, adjuvant drugs such as NMJ blockers are used to create increased muscle relaxation without increasing anesthetic dose. NMJ blockers fall into two major classes: nicotinic antagonists which block the actions of ACh and depolarization blockers which hyper-stimulate the NMJ producing depolarization blockade. In addition, several venoms act to block the NMJ.
Name 3 NMJ non-depolorizing blockers.
atracurium
pancuronium
rocuronium
What is the mechanism of action for atracurium, pancuronium, and rocuronium?
What are the effects of these drugs?
Clinical uses?
Toxicities?
Describe the solubility and distribution of these drugs. Which is the most long acting drug?
The non-depolarizing blockers are NMJ direct-acting antagonists in the classical sense that they occupy the receptor, and prevent binding by ACh. The prototypical agent is d-tubocurarine, although this drug has mostly been replaced with a host of other drugs including atracurium and the steroid NMJ blockers including pancuronium and rocuronium as well as vecuronium.
- MOA: these drugs are competitive antagonists at the NMJ with “surmountable affinity” for the Nm receptor (AChEI reversible). D-tubocurarine has some affinity for Nn receptors at higher doses and can produce SANS and PANS effects leading to the use of the other agents which have significantly lower affinity for Nn.
- Effects are dose dependent NMJ blockade leading to weakness and eventually flaccid paralysis. The blockade is surmountable.
- Clinical: used mostly in surgery but also for intubations.
- Toxicity is related to NMJ blockade and at very high doses, can produce complete respiratory compromise necessitating ventilation. D-tubocurarine stimulates the release of histamine and many of the other drugs do as well which can lead to hypotension. Toxicity, however, is mostly dose-dependent and would interact with any other drug that produces muscle weakness.
- Pharmacokinetic considerations are notable here in that all of these drugs are poorly lipid soluble and primarily have peripheral effects. Their other PK characteristics determine their durations of action and whether or not they are metabolized. Pancuronium is the long-acting agent in this class.
How are non-depolarizing blockers reversed?
Reversal of blockade—neostigmine (must be given with atropine to prevent muscarinic effects such as bradycardia), edrophonium, and other cholinesterase inhibitors.
What drugs are considered to be depolarization blockers?
The depolarization blockers would include all AChEIs, ACh itself, and succinylcholine. Structurally succinylcholine is a combination of two ACh molecules.
State th following facts for succinylcholine:
Mechanism of action (MOA)
Effects
Clinical uses
Toxicity
MOA: it is a full and specific agonist at Nm receptors that primarily blocks the NMJ by inducing depolarization blockade that occurs in two phases.
a. Phase I: By occupying the receptor, succinylcholine continues to agonize the receptor preventing the motor end plate from re- polarizing. Re-polarization is needed to reset excitation- contraction coupling (re-priming) and the NMJ is effectively blocked.
b. Phase II: The mechanism here is not completely understood, but with the eventual diffusion away from the receptor, the receptor is no longer able to be activated, even by higher than normal ACh levels. This desensitization phase slowly recovers, allowing for normal function to eventually develop.
2. Effects of succinylcholine start with muscle fasciculations as depolarization blockade develops, followed by flaccid paralysis with slow recovery.
3. Clinical use is almost exclusively in muscle relaxation for surgery.
4. Toxicity is minimal with the exception of muscle paralysis that can require ventilation.
a. Bolus injection can release histamine and produce hypotension.
b. Bolus injection can increase intraocular pressure so that patients with glaucoma are in greater jeopardy.
c. It releases K+ from several sites in the body leading to hyperkalemia. This is especially true in burn patients.
What is responsible for the metabolism of succinylcholine?
What is the clinical relevance of this?
Pharmacokinetic considerations are related to butyrylcholinesterase which is exclusively responsible for breaking succinylcholine down. There is genetic variation in butyrylcholinesterase and some patients have genetic variants that result in poor biotransformation with excessively prolonged NMJ blockade that can be life-threatening. Because of Phase II, this blockade is not surmountable and would necessitate prolonged ventilation.
a. These genetic variants can be assessed prior to surgery by taking a serum sample and assessing the inhibition of butyrylcholinesterase using dibucaine. A normal dibucaine number is 80% inhibition whereas a lower number flags a genetic variant and the chance of extended desensitization blockade.
Explain the mechanism of action (MOA) of the following toxins
alpha-bungarotoxin
alpha-latrotoxin
α-Bungarotoxin is one of the components of the venom of the elapid snake that also includes cobras and coral snakes that binds to, and inhibits the NMJ similar to curare (competitive irreversible AChR antagonist)
alpha-latrotoxin, is in the venom of widow spiders and produces the presynaptic release of neurotransmitters (including acetylcholine) from sensory and motor neurons. It produces depolarization blockade similar to that of succinylcholine. It binds to the vesicles and facilitates their binding to the presynaptic membrane via synaptotagmin.
How do ganglionic blockers work? Give an example of a ganglionic blocker.
Ganglionic blockers: This group of drugs takes advantage of the difference in the esteric and anionic sites on the ACh receptor. The space between these two sites is narrower for the Nn receptor and thus drugs with shorter distances between the moieties that bind to these sites can produce relatively specific effects at NN receptors without significant blockade of Nm sites. Because they block all ANS outflow, they have numerous side effects and therefore limited clinical efficacy. They remain important research drugs, however. Note “hexa” and “tri” below indicating the carbon length.
A. Mecamylamine, hexamethonium, and trimethaphan are the primary drugs used.
