Neuromuscular Blocking Drugs: Pharmacology

Lecture Objectives

• The lecture discusses the pharmacology of drugs that induce skeletal muscle paralysis, increase muscle strength and treat spastic disorders.

AP Propagation

• An action potential triggers the release of acetylcholine (ACh).
• ACh stimulates nicotinic Na+ channels, leading to an action potential.
• This then stimulates voltage-sensitive Na+ channels, resulting in AP propagation.

Neuromuscular Junction

• The arrival of an action potential at a nerve results in the release of acetylcholine.
• Acetylcholine travels in the synaptic cleft, stimulating channels to develop an endplate potential.
• The depolarization propagates down the muscle via the channels.
• This action is terminated by an enzyme.

Neuromuscular Blocking Drugs

• There are two types: non-depolarizing and depolarizing.
• Non-depolarizing drugs like Mivacurium and Pancuronium competitively block nicotinic receptors, inhibiting ACh.
• Depolarizing drugs, like Succinylcholine, cause persistent depolarization, blocking action potential passage through voltage-gated sodium channels.
• These drugs are used clinically for muscle relaxation during general anesthesia and endotracheal intubation.

Chemistry of Neuromuscular Blocking Drugs

• They contain charged N groups, are similar to ACh, and are very polar.

Pharmacokinetics of Certain Drugs

• Route of administration: IM or IV
• Dosage: Usually 0-3-1mg/kg BW by IV
• Onset: Less than 5 minutes

Duration of Action for Certain Drugs

• Ultrashort (5-10 mins): Succinylcholine, Mivacurium
• Long-acting (30-120 mins): Pancuronium

Metabolism and Elimination of Certain Drugs

• Succinylcholine and Mivacurium are metabolized by pseudocholinesterases.
• Pancuronium is eliminated renally.

Adverse Drug Reactions

• Muscle fasciculation with succinylcholine can cause post-operative pain.
• Other adverse reactions include histamine release and hyperkalemia.
• Malignant hyperthermia is a genetic disorder of skeletal muscle calcium regulation, causing uncontrolled skeletal muscle hypermetabolism, that can be triggered by Succinylcholine

Skeletal Muscle Relaxants

• Used to relieve spasticity in conditions like cerebral palsy, multiple sclerosis, spinal cord injury, and stroke.
• Dantrolene inhibits the release of Ca2+ from the sarcoplasmic reticulum, preventing excitation-contraction coupling.

Baclofen

• Acts as an agonist at GABA-B receptors in the spinal cord.
• It reduces motor neuron activation by acting on pre- and post-synaptic receptors.

Diazepam

• Potentiates GABA-A activity.
• It decreases motor neuron activation in the spinal cord and brain.

Pharmacokinetics of Relaxants

• Baclofen has good oral absorption and is widely used; it is eliminated renally.
• Dantrolene is hepatotoxic and requires monitoring; it is eliminated hepatically.
• Diazepam has good oral absorption, active metabolites, and causes significant sedation; it is eliminated hepaticaly.

Pyridostigmine

• Mechanism of action: Reversibly inhibits acetylcholinesterase, leading to acetylcholine accumulation.
• Route: Orally, well-absorbed.
• Elimination: Renal.
• Clinical applications: Improves muscle strength in patients with myasthenia gravis.
• Side effects: Salivation, anorexia, nausea, vomiting, abdominal cramps, diarrhea, muscle cramps, fasciculation, weakness, and cholinergic crisis.