Why do aminoglycosides cause paralysis? Unpacking the neuromuscular blockade

October 6, 2025 •

3 min read

Over 25 years ago, it was already known that certain antibiotics could induce skeletal muscle paralysis. This effect is a significant adverse reaction of the aminoglycosides, which cause paralysis by disrupting the signaling process at the neuromuscular junction, leading to muscle weakness and potential respiratory failure.

Quick Summary

Aminoglycosides cause neuromuscular blockade and potential paralysis by inhibiting acetylcholine release presynaptically and reducing acetylcholine receptor sensitivity postsynaptically, a risk heightened in patients with neuromuscular disorders or on certain medications.

Key Points

Dual Mechanism: Aminoglycosides cause paralysis by blocking nerve impulses at the neuromuscular junction via two distinct mechanisms: presynaptic inhibition and postsynaptic desensitization.
Presynaptic Action: They inhibit the release of acetylcholine, the neurotransmitter required for muscle contraction, by interfering with the influx of calcium ions into the nerve terminal.
Postsynaptic Action: At higher concentrations, aminoglycosides can also reduce the sensitivity of the muscle's acetylcholine receptors, diminishing its response to any remaining neurotransmitter.
High-Risk Patients: The risk of paralysis is significantly higher in individuals with pre-existing neuromuscular disorders, such as myasthenia gravis, or those also receiving neuromuscular-blocking agents or calcium channel blockers.
Clinical Signs: Symptoms range from muscle weakness to severe respiratory depression and apnea, requiring immediate intervention.
Reversal: The effects can often be reversed by the intravenous administration of a calcium salt, which counteracts the drug's inhibitory effects on calcium signaling.

The neuromuscular junction (NMJ) is the critical synapse between a motor neuron and a skeletal muscle fiber, where nerve signals are converted into muscle contractions. A motor neuron releases the neurotransmitter acetylcholine (ACh) into the synaptic cleft, which then binds to receptors on the muscle fiber's motor end plate, triggering muscle depolarization and contraction. Any interference with this delicate process can lead to muscle weakness or paralysis.

The Dual Mechanism of Aminoglycoside-Induced Paralysis

Aminoglycoside-induced neuromuscular blockade is not a simple one-step process. Research has revealed a dual mechanism involving both the presynaptic nerve terminal and the postsynaptic muscle membrane.

Presynaptic Blockade: Impaired Acetylcholine Release

The primary mechanism involves the inhibition of acetylcholine release from the presynaptic nerve terminal. This is mediated by the antibiotic's interaction with calcium channels and calcium-sensing receptors (CaSR).

Calcium Channel Interference: Aminoglycosides interfere with the movement of calcium ions ($Ca^{2+}$) across the presynaptic nerve ending membrane. The influx of calcium through voltage-gated calcium channels is a necessary step for triggering the release of acetylcholine from vesicles into the synaptic cleft. By blocking these channels, aminoglycosides effectively reduce the amount of ACh released, diminishing the signal to the muscle.
Competitive Antagonism with Calcium: Some studies suggest that aminoglycosides act as competitive antagonists of calcium at presynaptic sites required for transmitter release. By binding to the calcium ion-binding site, the drugs prevent calcium from fulfilling its role in exocytosis.

Postsynaptic Blockade: Receptor Desensitization

In addition to the presynaptic effects, some aminoglycosides also exert a postsynaptic blocking action.

Reduced Receptor Sensitivity: At higher concentrations, aminoglycosides can reduce the sensitivity of acetylcholine receptors on the motor end plate. This means that even if some acetylcholine is released, it is less effective at stimulating the muscle fiber to contract, further contributing to muscle weakness.
End-Plate Ionic Conductance Blockade: The drugs can also block the receptor-activated ion channels, preventing the necessary flow of ions like sodium that leads to muscle depolarization.

Risk Factors and Clinical Implications

While uncommon, the risk of aminoglycoside-induced neuromuscular blockade and paralysis is significantly elevated in certain situations.

Patient-specific risk factors:

Pre-existing Neuromuscular Disorders: Patients with conditions like myasthenia gravis or parkinsonism are highly susceptible to prolonged or severe neuromuscular blockade. In myasthenia gravis, the body's own antibodies already attack ACh receptors, making any further disruption catastrophic.
Renal Impairment: Kidney dysfunction can lead to elevated serum concentrations of aminoglycosides, increasing the risk of toxicity.
Advanced Age: Elderly clients often have reduced renal function and other comorbidities that increase their vulnerability to neurotoxicity.

Administration-related risk factors:

Concurrent Medications: The risk increases dramatically when aminoglycosides are co-administered with other drugs that affect the neuromuscular junction. These include general anesthetics and other neuromuscular-blocking agents like succinylcholine or curare-like drugs.
Rapid Intravenous Administration: Rapid IV infusion or high-dose intraperitoneal/intrapleural instillation increases the likelihood of reaching toxic concentrations and inducing blockade.

Clinical Manifestations and Management

Early signs of neuromuscular blockade may include general muscle weakness, which can progress to respiratory muscle paralysis and apnea. This is a medical emergency requiring immediate attention. If signs of respiratory paralysis occur, the aminoglycoside should be discontinued, and the patient may require mechanical respiratory assistance.

Fortunately, aminoglycoside-induced neuromuscular blockade is often reversible. Administering a calcium salt, such as calcium chloride or calcium gluconate, can help reverse the effect by increasing the calcium concentration and overcoming the drug's blocking action.


Feature	Presynaptic Mechanism	Postsynaptic Mechanism
Primary Effect	Inhibits acetylcholine (ACh) release	Reduces ACh receptor sensitivity
Target Location	Nerve terminal membrane	Muscle fiber end-plate
Key Interference	Calcium ($Ca^{2+}$) influx and function	ACh receptor binding and ion channel function
Dominant Action	Primarily responsible for blockade	Contributes, especially at higher concentrations
Reversal Agent	Reversed by increasing calcium levels	Reversal is more complex; calcium helps

Conclusion

While aminoglycoside-induced paralysis is a rare adverse effect, its potentially fatal consequences make understanding its mechanism crucial. The dual-action blockade at the neuromuscular junction—inhibiting acetylcholine release presynaptically and desensitizing receptors postsynaptically—is the root cause. This risk is exacerbated in patients with pre-existing neuromuscular disease and with certain drug combinations, particularly during rapid administration. Clinicians must be vigilant in monitoring at-risk patients and prepared to administer calcium salts to reverse the effects of this potentially life-threatening complication.

For more detailed information on antibiotic-associated neurotoxicity, you can consult a review article on the topic.

Frequently Asked Questions

Aminoglycosides primarily cause paralysis by blocking the release of acetylcholine, the neurotransmitter responsible for muscle contraction, from the nerve terminal at the neuromuscular junction.

Aminoglycosides interfere with acetylcholine release by blocking the influx of calcium ions ($Ca^{2+}$) into the nerve terminal. Calcium is essential for initiating the release of acetylcholine from synaptic vesicles.

No, while the presynaptic effect is a major contributor, some aminoglycosides also exert a postsynaptic effect by reducing the sensitivity of acetylcholine receptors on the muscle end-plate, further weakening the muscle's response.

Patients with pre-existing neuromuscular diseases like myasthenia gravis or parkinsonism are at significantly higher risk. The risk is also increased in those with renal impairment, advanced age, or rapid intravenous administration.

The risk is amplified when aminoglycosides are given with other neuromuscular-blocking agents (like succinylcholine or curare) or calcium channel blockers.

Signs include general muscle weakness that can potentially lead to respiratory failure and apnea due to paralysis of the respiratory muscles.

Treatment involves discontinuing the drug and administering a calcium salt, such as calcium chloride, intravenously. Mechanical respiratory assistance may also be necessary in severe cases.