18. PERIPHERAL MUSCLE RELAXANT DRUGS Flashcards
Explain the nicotinic cholinergic receptor:
- Transmembrane ion-channel receptor
- Alpha units are the ligand (ACh) ocupation sites.
- ACh activates the influx of Na+ and efflux of K+
- Depolarizing agents act similarly to Ach.
- Nondepolarizing agents antagonise the ACh competively
Classes of neuromuscular blocking agents:
- Depolarizing neuromuscular blocking agents (succinylcholine)
- Competitive (non-depolarizing) neuromuscular blocking agents (prototype: dtubocurarine/curare)
What are the Uses of neuromuscular blocking agents?
By intravenous or systemic administration:
– Surgical anesthesia to obtain relaxation of skeletal muscle
– to minimize anesthetic use without compromising analgesia.
– To assist in intubation
– Corneal or retinal surgeries to obtain relaxation of extraocular muscles (cisatracurium)
– Therapy of spastic disorders
By topical administration:
– Mydriasis in birds (e.g. vecuronium)
NEUROMUSCULAR BLOCKING DRUGS DO NOT PRODUCE ——-
ANALGESIA!!!!
Mechanism of succinylcholine:
Mechanism:
-Stimulate opening of nicotinic ACh receptor channel and produce depolarization of the cell membrane;
- Succinylcholine persists at the neuroeffector junction and activates the nicotinic receptor channels continuously, which results in inactivation of voltage-gated sodium channels so that they cannot reopen to support further action potentials (sometimes called “depolarizing blockade”)
Why is succinylcholine chloride used?
Used to facilitate intubation (mostly in humans); used illegally in bow hunting or „euthanasia”.
- In an emergency can be given IM, but slower and less predictable action.
What can succinylcholine chloride cause?
- Bradycardia (atropine can prevent)
- hyperkalaemia
- increased intra-ocular and intragastric pressure
- anaphylaxis
- malignant hyperthermia in genetically predisposed subjects.
- Dogs, cattle, sheep sensitive; horses and pigs less.
Depolarizing blocking agents: Phase 1
Phase I block
– depolarizing block of motor end-plate.
Phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors.
Depolarizing blocking agents: Phase 2
Phase II block – side effect, After repolarisation the membrane cannot easily be depolarized again
Depolarizing agents: How is the onset of action?
rapid (1min)
Depolarizing agents: How is the duration of action?
Duration of action - short; however may revert to phase II block
Depolarizing agents: How is the effect?
The effect is rather predictable
Depolarizing agents: termination of action?
Termination of action: metabolized by plasma pseudocholinesterase and liver
Depolarizing agents: who is the initial metabolite?
Initial metabolite is succinylmonocholine, weaker, predominately competitive blocking action.
Depolarizing agents: how is the effect on skeletal musle?
- fasciculation “muscle twitch” - weakness - paralysis
Depolarizing agents: how is the effect on cardiovascular system?
Effect on cardiovascular system:
- increased blood pressure
- increased or decreased heart rate (due to stimulation of parasympathetic and/or sympathetic ganglia)
- Bradycardia occurs after repeated use more frequently (Atropine)
By who is the activity of depolarizing agents enhanced?
Activity enhanced or potentiated by neostigmine and organophosphates (cholinesterase inhibitors), isoflurane.
What are the undesirable side effects? (depolarizing agents)
- muscle fasciculation
- hyperkalemia
– Phase II block
– May trigger malignant hyperthermia in genetically susceptible patients (dyspnea, tremor and stiffness, extreme hyperthermia, and rapid postmortem rigor mortis)
– Muscarinic actions at high doses
advantages of depolarizing agents?
Advantages - short duration of action, little histamine release
Competitive - nondepolarizing - neuromuscular blocking agents: Mechanism:
Selectively antagonize nicotinic receptors, thus preventing endogenous ACh binding and subsequent muscle cell depolarization (sometimes called “nondepolarizing blockade”)
What are some Competitive neuromuscular blocking agents: GROUPS
-BENZYLISOQUINOLINE group
A-MINOSTEROID group
-OTHERS: gallamine
BENZYLISOQUINOLINE group:
- d-tobocurarine
- Atracurium (imp)
- Cisatracurium (imp)
- Mivacurium Metabolism in blood plasma Histamine release
AMINOSTEROID group
- Pancuronium
- Vecuronium
- Rocuronium Metabolism in liver
No histamine release
Classification of the agents based on their duration of action:
Ultra-short duration:
-Gantacurium
Short duration: Mivacurium
-Chandonium
Intermediate duration:
- Atracurium
- Cisatracurium
- Fazadinium
- Rocuronium
- Vecuronium
Long duration:
- Doxacurium
- Dimethyltubocurarine
- Pancuronium
- Pipecuronium
- Laudexium
- Gallamine
Effect of competitive blockers on cardiovascular system
- Decreased blood pressure - due to histamine release (benzylisoquinolines)
- Increased heart rate (baroreceptor reflex)
- Coagulability of blood decreased (due to release of heparin from mast cells)
Competitive neuromuscular blocking agents – long acting
d-tubocurarine (BI)
- slight hypotension and tachycardia; histamine (HA) release (problem in asthma), excretion via urine (in kidney disease delayed); Long-acting. Limited use.
-Gallamine (O)
tachycardia and hypertension; no HA release (only in very large doses); Long-acting. Crosses placental barrier. Frequently used in human surgery.
-Pancuronium (AS)
long-acting; slight tachycardia and hypertension. Metabolism in liver, elimination via urine. Liver and kidney disease prolongs its effect.
Competitive neuromuscular blocking agents benzylisoquinolines: • Atracurium (BI)
• Atracurium (BI) (ATRACURIUM BESILATE KALCEKS® 10 mg/ml inj., TRACRIUM ® 10 mg/ml inj.) - intermediate-acting; - safe in liver and kidney disease (metabolism in plasma); - bradycardia may occur during surgical manipulations, esp. ophthalmologic, or laparoscopy (treat with atropine or glycopyrrolate); - precipitates in alkaline pH; - can cause HA release at higher doses. Probably most used in veterinary medicine.
Competitive neuromuscular blocking agents - benzylisoquinolines • Cisatracurium (BI)
Cisatracurium (BI) (CISATRACURIUM KALCEKS ® 2 mg/ml inj.) – R-cis isomer of atracurium; 3X potency; immediate onset of action; intermediate-acting; metabolism in plasma; used in ophthalmologic surgeries.
Competitive neuromuscular blocking agents - benzylisoquinolines • Mivacurium (BI)
• Mivacurium (BI) – short acting, succinylcholine alternative developed for human use; HA release, hypotension can occur; meatabolism in plasma (esterases)
Competitive neuromuscular blocking agents -aminosteroids • Rocuronium (AS)
• Rocuronium (AS) (ESMERON® inj., ROCURONIUM KALCEKS® inj.) Due to very fast onset of action is a succinylcholine alternative developed for human use. intermediateacting; metabolism in liver; excretion with bile; lack of CV or HA-releasing effects but may cause anaphylactic reaction quite frequently.
Vecuronium (AS) -
Vecuronium (AS) - intermediate-acting; lack of CV or HA-releasing effects; drug of choice when CV stability required; metabolism in liver; excretion with bile and urine; Causes mydriasis in birds.
Competitive blockers
Action antagonized by cholinesterase inhibitors (neostigmine, pyridostigmine, edrophonium), or tetanic stimulation (a 50-Hz electrical stimulation given for 5 seconds) • The muscarinic side-effect of neostigmine has to be controlled with Atropine.
