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25 Cards in this Set

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What is Cholinergic Receptor Blockade?
Previously, drugs that bind to but do not activate receptors have been defined as receptor antagonists. Often antagonists are called "receptor blockers" because they produce functional "receptor blockade" (inaccessibility of the receptors to agonists). Antagonists at a particular type of receptor block information transmission at synapses where those receptors are present - recall that any transmitter should be considered as an agonist for the receptors present at synapses mediated by that transmitter.
antagonists at muscarinic receptors are therefore often referred to as "_________________" and, antagonists at nicotinic receptors are often referred to a "________________".
muscarinic receptor blockers
nicotinic receptor blockers
Functional blockade of cholinergic synapses mediated by _______ can also be induced by _______________
nicotinic receptors
nicotinic agonists.
nicotinic agonists can induce?
receptor desensitization (functional uncoupling of the receptor from the effector mechanism to which it is normally coupled).
Although not actually "nicotinic receptor blockers" (i.e. they are not receptor antagonists), nicotinic agonists do produce “_____________" and for brevity may be referred to as being "nicotinic receptor blockers".
"blockade of cholinergic synapses mediated by nicotinic receptors”
Where are Nicotinic Receptor Blockers Effective?
At any synapse where acetylcholine is neurotransmitter AND postsynaptic receptors are nicotinic.
The nicotinic receptors are found in ______, in the _________ and at the _________________________.
the CNS
autonomic ganglia
skeletal neuromuscular junction (NMJ).
there are two types of nicotinic receptor - NN and NM - so that it is possible to target?
either the receptors on neurons (NN) or those at NMJs (NM) by selection of drugs with high affinity for one type of nicotinic receptor or the other.
What drugs are nicotinic receptor antagonists which block the skeletal NMJ?
curare (TUBARINE), atracurium (TRACRIUM) and gallamine (FLAXEDIL)
What are the effects of and clinical uses of nicotinic receptor antagonists which block the skeletal NMJ?
Use of a competitive NM receptor antagonist such as curare (TUBARINE), atracurium (TRACRIUM) and gallamine (FLAXEDIL) to prevent binding of ACh to these receptors on the skeletal muscle fibers reduces the effects of ACh released from the motor neurons.

The effect is to cause muscle relaxation or flaccid paralysis. This is an important clinically desirable effect in many surgical applications, for tracheal intubation (insertion of a tube into the trachea to aid normal breathing or to permit artificial ventilation) and during electrical convulsant treatment (ECT, still used effectively for certain nervous problems).

These are generally long acting drugs (about one hour for a normal dose).
What is Curare?
a natural, plant-derived compound, is the prototypic drug and is very effective in inducing skeletal muscle relaxation; however it also causes vasodilation and significant reduction of blood pressure (as a result of curare-induced histamine release from mast cells). Curare is an nicotinic receptor antagonist
What are atracurium and gallamine
The synthetic compounds, atracurium and gallamine are effective muscle relaxants but do not induce histamine release - thus making them advantageous for clinical use. Both are nicotinic receptor antagonists
An important feature of all three of these nicotinic receptor antagonists is?
that their effect in causing muscle relaxation is inversely related to the density of motor innervation: consequently, paralysis of the muscles of the face, limbs and trunk can be achieved without paralysis of the diaphragm and thus without jeopardy to the patient which would follow from paralysis of this critical respiratory muscle. (That said, artificial ventilation might be expected to be used whenever these agents are used!)
Also these competitive antagonists at NM receptors have a greater duration of action than so called non-competitive or desensitizing blockers of the NMJ - the competitive NM receptor antagonists are eliminated more slowly - and that the competitive NM receptor antagonists are not substrates for cholinesterases.
What are the effects of and clinical uses of nicotinic receptor agonists which functionally block the skeletal NMJ?
Use of a NM receptor agonist succinylcholine (SCh; ANECTINE) to cause receptor desensitization (uncoupling of receptors from the contractile mechanism of the muscle) also causes muscle relaxation or flaccid paralysis.

SCh is known as a non-competitive or desensitizing blocker of the NMJ.

The effect of SCh is shorter (a few minutes for a single dose) than that of the competitive antagonists at these receptors because it is rapidly eliminated in part because Sch is a substrate for ChEases.

SCh seems to have greater effects on muscle of the limbs and trunk so that respiratory activity (dependent on activation of the diaphragm) is usually unaffected. (That said, it would be normal that patients treated with SCh would be artificially ventilated!)
A NN receptor antagonist prevents binding of ACh to these receptors on postganglionic neurons reduces the effects of ACh released from preganglionic neurons?
trimethaphan (ARFONAD)
What are the effects of nicotinic receptor antagonists and agonists which functionally block synaptic transmission in autonomic ganglia?
A NN receptor antagonist such as trimethaphan (ARFONAD) prevents binding of ACh to these receptors on postganglionic neurons reduces the effects of ACh released from preganglionic neurons
this drug is a competitive antagonist at those receptors and thus a competitive blocker of cholinergic transmission in the ganglia.
trimethaphan (ARFONAD)
The effect of trimethaphan (ARFONAD) is to?
decrease frequency of action potentials generation in the cell body of each postganglionic neuron and propagated to each axon terminals.

receptor desensitization (uncoupling of receptors from the action potential generating mechanisms of the postganglionic neuron) also decreases the frequency of action potentials (generated in the cell body of each postganglionic neuron and propagated to its axon terminals);
Use of a NN receptor agonist such as nicotine to cause?




This drug is a non-competitive, desensitizing blocker of cholinergic transmission in the ganglia.
trimethaphan (ARFONAD)
Both the nicotinic receptor antagonist and the nicotinic receptor agonist are effective in producing?
functional blockade of synapses between preganglionic neurons and postganglionic neurons.
The effect of functional blockade of synapses in autonomic ganglia is difficult to predict because?
these drugs can not selectively target the ganglia of either the sympathetic nervous system or the parasympathetic nervous system - both systems are affected. Thus the effect of functional blockade depends on the tone of each system. One might expect that functional blockade of autonomic ganglia in an individual at rest when the parasympathetic nervous system is dominant would be to induce effects similar to those of decreased activity of the PNS or increased activity of the SNS. Conversely one might expect that autonomic blockade in an individual in whom the flight or fright reflex (i.e., the SNS) has been activated would be to induce effects similar to those of increased activity of the PNS or of decreased activity of the SNS.

In other words, these compounds can be difficult to use clinically!!
What are the clinical uses of nicotinic receptor antagonists and agonists which functionally block synaptic transmission in autonomic ganglia?
Functional autonomic blockade is useful to reduce blood pressure in hypertensive crisis and to reduce hemorrhage during surgery.

The effect of autonomic blockade on the heart is essentially a "no effect" mostly because block of SNS induced positive chronotropic effects are countered by block of PNS induced negative chronotropic effects. However, reduced SNS output to arterioles causes dilation of these vessels and thus reduces blood pressure. Additionally, reduced SNS output to veins causes dilation of these vessels so that more blood pools in these vessels and less blood is returned to the heart; consequently, cardiac output is decreased and blood pressure is reduced. Importantly, the reduced blood pressure cause by vessel dilation caused by autonomic ganglion blockade can not be countered by reflex increased heart rate (because of the ganglion blockade!).
In the case of hypertensive crisis, blood pressure can be lowered to a safe level by?
ganglionic blockade although this approach is not satisfactory for treating chronic hypertension.
In the case of hemorrhage during surgery, the ganglionic blockade induced reduction of blood pressure does what?
reduces perfusion of blood through all vessels and thus will tend to reduce bleeding from injured or cut blood vessels.
Important Considerations when using any Agent to Cause Functional Blockade at the Skeletal NMJ
These drugs produce muscle relaxation; they do not anesthesia or lack of consciousness. These drugs should be administered in conjunction with a general anesthetic - think how scared you would be if you had been given one of these drugs in the absence of a general anesthetic...you would be paralyzed but totally conscious and sensitive to all stimuli!!
The muscle fibers are functionally normal - will contract if appropriately stimulated (e.g. application of an electric shock) after (flaccid) paralysis has been induced by these drugs.
The effects of competitive nicotinic receptor antagonists to induce muscle relaxation can be reversed using a CHEase inhibitor (to prevent ACh metabolism in the synaptic gap) but that a CHEase inhibitor will not reverse the muscle relaxant effect of SCh (and indeed the effects may be exacerbated).