Neurotransmission at adrenergic neurons

Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons , except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps:synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap

Figure: Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)

1. Synthesis of norepinephrine:

Tyrosine is transported by a Na +-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.1 This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron. 

2. Storage of norepinephrine in vesicles:

Dopamine is then trans-ported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is blocked by reserpine .Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase.

 [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP), and β-hydroxylase, as well as other cotransmitters.] In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of which are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation

3. Release of norepinephrine: 

An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. This release is blocked by drugs such as guanethidine .

4. Binding to a receptor:

 Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system,2 and the phosphatidylinositol cycle,3 to transduce the signal into an effect.

5. Removal of norepinephrine:

Norepinephrine may
1) diffuse out of the synaptic space and enter the general circulation

2) be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space, or
 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium/potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see Figure above). 

Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine's effects. 

6. Potential fates of recaptured norepinephrine: 

Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine.

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Depolarizing agents

1. Mechanism of action:

The depolarizing neuromuscular blocking drug succinylcholine [suk-sin-ill-KOE-leen] attaches to the nicotinic receptor and acts like acetylcholine to depolarize the junction.

Figure : Mechanism of action of depolarizing neuromuscular blocking drugs.


Unlike acetylcholine, which is instantly destroyed by acetylcholinesterase, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing a constant stimulation of the receptor. [Note: The duration of action of succinylcholine is dependent on diffusion from the motor end plate and hydrolysis by plasma cholinesterase.].

 The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor (Phase I). This leads to a transient twitching of the muscle (fasciculations). Continued binding of the depolarizing agent renders the receptor incapable of transmitting further impulses. With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked. This causes a resistance to depolarization (Phase II) and a flaccid paralysis.

2. Actions:

The sequence of paralysis may be slightly different, but as with the competitive blockers, the respiratory muscles are paralyzed last. Succinylcholine initially produces short-lasting muscle fasciculations, followed within a few minutes by paralysis. The drug does not produce a ganglionic block except at high doses, but it does have weak histamine-releasing action. Normally, the duration of action of succinylcholine is extremely short, because this drug is rapidly broken down by plasma cholinesterase.

 However, succinylcholine that gets to the neuromusclular junction is not metabolized by acetylcholinesterase, allowing the agent to bind to nicotinic receptors, and redistribution to plasma is necessary for metabolism (therapeutic benefits last only for a few minutes). [Note: Genetic variants in which plasma cholinesterase levels are low or absent leads to prolonged neuromuscular paralysis

3. Therapeutic uses: 

 Because of its rapid onset and short duration of action, succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia (a rapid action is essential if aspiration of gastric contents is to be avoided during intubation). It is also employed during electroconvulsive shock treatment.


4. Pharmacokinetics:

Succinylcholine is injected intravenously. Its brief duration of action (several minutes) results from redistribution and rapid hydrolysis by plasma cholinesterase. It therefore is usually given by continuous infusion.


 5. Adverse effects

a. Hyperthermia: When halothane  is used as an anesthetic, administration of succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity and hyperpyrexia) in genetically susceptible people . This is treated by rapidly cooling the patient and by administration of dantrolene, which blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells, thus reducing heat production and relaxing muscle tone

b. Apnea: Administration of succinylcholine to a patient who is genetically deficient in plasma cholinesterase or has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm. c. Hyperkalemia: Succinylcholine increases potassium release from intracellular stores. This may be particularly dangerous in burn patients or patients with massive tissue damage in which postassium is been rapidly lost from within cells.

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Nondepolarizing (competitive) blockers

The first drug that was found to be capable of blocking the skeletal neuromuscular junction was curare, which the native hunters of the Amazon in South America used to paralyze game.

The drug tubocurarine [too-boe-kyoo-AR-een] was ultimately purified and introduced into clinical practice in the early 1940s. Although tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents due to side effects . The neuromuscular blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery. Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing recovery time after surgery.]

 1. Mechanism of action:

a. At low doses: Nondepolarizing neuromuscular blocking drugs interact with the nicotinic receptors to prevent the binding of acetylcholine

Figure : Mechanism of action of competitive neuromuscular blocking drugs.


These drugs thus prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with acetylcholine at the receptor without stimulating the receptor, they are called competitive blockers. Their action can be overcome by increasing the concentration of acetylcholine in the synaptic gap—for example, by administration of cholinesterase inhibitors, such as neostigmine, pyridostigmine, or edrophonium. Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade

b. At high doses: Nondepolarizing blockers can block the ion channels of the end plate. This leads to further weakening of neuromuscular transmission, and it reduces the ability of acetylcholinesterase inhibitors to reverse the actions of nondepolarizing muscle relaxants.


 2. Actions:

Not all muscles are equally sensitive to blockade by competitive blockers. Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck, and trunk muscles are paralyzed. Then the intercostal muscles are affected, and lastly, the diaphragm muscles are paralyzed. Those agents (for example, tubocurarine, mivacurium, and atracurium), which release histamine, can produce a fall in blood pressure, flushing, and bronchoconstriction.


3. Therapeutic uses:

These blockers are used therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle. These agents are also used to facilitate intubation as well as during orthopedic surgery.


4. Pharmacokinetics:

All neuromuscular blocking agents are injected intravenously, because their uptake via oral absorption is minimal. These agents possess two or more quaternary amines in their bulky ring structure, making them orally ineffective. They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier. Many of the drugs are not metabolized; their actions are terminated by redistribution.

Figure: Pharmacokinetics of the neuromuscular blocking drugs. IV = intravenous.


 For example, tubocurarine, pancuronium, mivacurium, metocurine, and doxacurium are excreted in the urine unchanged. Atracurium is degraded spontaneously in the plasma and by ester hydrolysis. [Note: Atracurium has been replaced by its isomer, cisatracurium. Atracurium releases histamine and is metabolized to laudanosine, which can provoke seizures. Cisatracurium, which has the same pharmacokinetic properties as atracurium, is less likely to have these effects.] The aminosteroid drugs (vecuronium and rocuronium) are deacetylated in the liver, and their clearance may be prolonged in patients with hepatic disease. These drugs are also excreted unchanged in the bile. The choice of an agent will depend on how quickly muscle relaxation is needed and on the duration of the muscle relaxation. 

5. Adverse effects:

In general, agents are safe with minimal side effects. The adverse effects of the specific neuromuscular blocking drugs are shown in Figure below .

Figure: Onset and duration of action of neuromuscular blocking drugs (center column), with a summary of therapeutic considerations.

6. Drug interactions:

a. Cholinesterase inhibitors: Drugs such as neostigmine, physostigmine, pyridostigmine, and edrophonium can overcome the action of nondepolarizing neuromuscular blockers, but with increased dosage, cholinesterase inhibitors can cause a depolarizing block as a result of elevated acetylcholine concentrations at the end-plate membrane. If the neuromuscular blocker has entered the ion channel, cholinesterase inhibitors are not as effective in overcoming blockade.

b. Halogenated hydrocarbon anesthetics: Drugs such as halothane act to enhance neuromuscular blockade by exerting a stabilizing action at the neuromuscular junction. These agents sensitize the neuromusclular junction to the effects of neuromuscular blockers.

c. Aminoglycoside antibiotics: Drugs such as gentamicin or tobramycin inhibit acetylcholine release from cholinergic nerves by competing with calcium ions. They synergize with tubocurarine and other competitive blockers, enhancing.

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ipratropium

Inhaled ipratropium [i-pra-TROE-pee-um], a quaternary derivative of atropine, is useful in treating asthma in patients who are unable to take adrenergic agonists. Ipratropium is also beneficial in the management of chronic obstructive pulmonary disease. It is inhaled for these conditions. Because of its positive charge, it does not enter the systemic circulation or the CNS, isolating its effects to the pulmonary system. Important characteristics of the muscarinic antagonists are summarized in Figures 5.6 and 5.7

Figure : Adverse effects commonly observed with cholinergic antagonists.


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Scopolamine

Scopolamine [skoe-POL-a-meen], another tertiary amine belladonna alkaloid, produces peripheral effects similar to those of atropine. However, scopolamine has greater action on the CNS (unlike with atropine, CNS effects are observed at therapeutic doses) and a longer duration of action in comparison to those of atropine. It has some special actions as indicated below.

 1. Actions: Scopolamine is one of the most effective anti–motion sickness drugs available

Figure : Scopolamine is an effective antimotion sickness agent.

 Scopolamine also has the unusual effect of blocking short-term memory. In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria and is subject to abuse.

2. Therapeutic uses: Although similar to atropine, therapeutic use of scopolamine is limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory. [Note: As with all such drugs used for motion sickness, it is much more effective prophylactically than for treating motion sickness once it occurs. The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures.]

3. Pharmacokinetics and adverse effects: These aspects are similar to those of atropine.

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