الحلقة 9 من كورس كلنيكال فارما (ANS)

Antinicotinic Agents

Neuromuscular Blockers (NMB)

- These drugs block cholinergic transmission between motor nerve endings and

the nicotinic receptors on the skeletal muscle.

- NMB are clinically useful during surgery to facilitate tracheal intubation and

provide complete muscle relaxation at lower anesthetic doses (lower anesthetic

doses ; allowing for more rapid recovery and reducing postoperative respiratory

depression).

- Classification according to mechanism of action.

A) Depolarizing NMB

B) Non-Depolarizing NMB (Competitive)

Non-Depolarizing NMB (Competitive)

Benzylisoquinolinium

Compounds

Amino-Steroid

Compounds

Miscellaneous

Curare Short Acting

Rapacuronium

(Raplon)

Gallamine (Flaxedil)

Tubocurarine (Tubarine)

Atracurium (Tracrium) Intermediate Acting

Rocuronium

(Esmeron)

Vecuronium

(Norcuron)

Cisatracurium (Nimbex)

Mivacurium (Mivacron) Long acting

Pancuronium

(Pavulon)

Pipecuronium

(Arduan)

Doxacurium (Nuromax)

Metocurine (Metubine)

- Curare is the first drug known to block the skeletal NMJ, which native South

American hunters of the Amazon region used to paralyze prey.

- Tubocurarine is the active agent of one of the forms of Curare, but it has been

replaced by other agents with fewer adverse effects.

- Atracurium is an intermediate-duration of action, it cause slight histamine

release (hypotension and bronchospasm) and is metabolized to toxic metabolite

called Laudanosine [law-DA- no-sen] wvhich can cause seizures. It has been

replaced by its isomer Cisatracurium.

- Cisatracurium is one isomers of the Atracurium, one of the most commonly used

(most popular) muscle relaxant and it have fewer side effects than Atracurium

(less histamine release & less Laudanosine).

- Mivacurium is a shortest-duration of action of all non-depolarizing NMB, it

cause histamine release. Clearance by plasma cholinesterase enzyme and may be

prolonged in patient with impaired renal function (due to: decrease in

cholinesterase enzyme). No longer used.

- Doxacurium is use has not been popular because of considerably long duration

of action, cause histamine release and metabolized into Laudanosine , greater

accumulation in individuals with renal failure.

- Rapacuronium is a short acting amino-steroid compounds and used in short

surgical operation, side effects include; hypotension, tachycardia and fatal

bronchospasm.

- Rocuronium and Vecuronium are metabolized in the liver and clearance may be

prolonged in patient with hepatic disease.

- Pancuronium is the one of three drugs administered during most lethal

injections in capital punishment in the United States. It is cause moderate

tachycardia because;

1) it has moderate parasympatholytic effect

2) ↑ NE release 3) prevent NE uptake.

- Lethal injection components: and cause respiratory depression lead to death.

(See CNS chapter)

1) Sodium thiopental (5 grams; 14 times the normal dose) induce

unconsciousness wvithin 10 sec.

2) Pancuronium bromide (100 milligrams) Paralysis of respiratory muscles will

lead to death.

3) Potassium chloride (100 milliequivalents) cause rapid cardiac arrest.

- Gallamine cause tachycardia and occasionally in blood pressure because;

1) it has strong parasympatholytic effect on the cardiac vagus nerve (Atropine like

effect on the heart via block M2 receptors).

2) It has sympathomimetic effect via ↑ norepinephrine (NE) release (Tyramine

like effect). It has no histamine release.

Pharmacokinetics:-

- All neuromuscular-blocking agents are highly polar (not pass BBB) compounds

and inactive orally; they must be administered parenterally.

- Pharmacokinetics properties:

Drug Elimination

Approximate

Duration of action

Approximate

potency

relative to

Tubocurarine

Tubocurarine Kidney (40%) >50min 1

Atracurium Spontaneous 20-35min 1.5

Cisatracurium Most

spontaneous

25-44min 1.5

Mivacurium Plasma ChE 10-20min 4

Rocuronium Liver (75-90%)

And Kidney

20-35min 0.8

Vecuronium 6

Pancuronium Kidney (80%) >35min 6

*Drugs taken safely in renal and hepatic impairment .... and ....

Mechanism of action:-

* At low dose → they compete with ACh at the nicotinic receptors at motor end

plate without stimulating → inhibition of muscle contraction.

- Their action can be overcome can by administration of cholinesterase

inhibitors, such as neostigmine.

* At high dose → they block the ion channels of the end plate → leading to

further weakening of neuromuscular transmission and reduce the ability of

anticholinesterase to reverse the action of non-depolarizing blockers. With

complete blockade, the muscle does not respond to direct electrical stimulation.

Pharmacological Action :-

- Not all muscles are equally sensitive to blockade.

- Small, rapidly contracting muscles of the face and eye are most susceptible and

are paralyzed first, followed by the fingers, limbs, neck, and trunk muscles. Next,

the intercostal muscles are affected and, lastly, the diaphragm.

- The muscles recover in the reverse manner.

Drug Effect on

Ganglia

Effect on cardiac

M2 receptor

Tendency to

cause histamine

release

Atracurium Weak block None Moderate

Tubocurarine None None Slight

Cisatracurium None None None

Mivacuriumn None None Moderate

Rocuronium None Slight None

Vecuronium None None None

Pancuronium None Moderate block None

Gallamine None Strong block None

* Drugs that cause histamine release are ..... , ..... , ......

* Drugs that cause decrease in blood pressure are .... & ....

Therapeutical uses :-

- Surgical relaxation; As adjuvants during general anaesthesia to provide skeletal

muscle relaxation.

- Endotracheal intubation; by relaxing pharyngeal and laryngeal muscles.

- Electro-convulsion therapy (ECT); to control muscle contraction.

Side Effects :-

- Tubocurarine → Hypotension due to histamine release and ganglionic blocker.

- Mivacurium > Atracurium → Hypotension due to histamine release.

- Gallamine > Pancuronium →Increase heart rate (tachycardia) → due to vagolytic action

(M2 blocked) and increase Noradrenaline release.

- Tubocurarine > Mivacurium> Atracurium→ bronchospasm due to histamine release

(Contraindicated in asthmatic patient).

Drug interactions :-

1) Cholinesterase inhibitors: such as Neostigmine and Physostigmine.

- Cholinesterase inhibitors can overcome the action of non-depolarizing neuromuscular blocker.

- If the neuromuscular blocker has block the ion channel, cholinesterase inhibitors are not as

effective in overcoming blockade.

2) Inhaled anesthetics: such as Halothane and Desfflurane.

- Inhaled anesthetics enhance non-depolarizing NMB effect by exerting a stabilizing action at

the NMJ → Additive effect.

3) Aminoglycoside antibiotics: such as Gentamicin and Tobramycin

- Aminoglycoside antibiotics inhibits ACh release from cholinergic nerves by competing with

calcium ions→ Synergistic effect.

4) Calcium channel blockers: These agents may increase the neuromuscular blockade of

competitive blockers.

Depolarizing NMB (Non-competitive)

Succinylcholine Decamethonium (Syncurine®)

Pharmacokinetics

Succinylcholine, also known as Suxamethonium.

- It is consists of two acetylcholine molecules that are linked together.

- It is duration of action is extremely short (<8 min) due to rapid

hydrolysis by kinetics plasma-ChE (Pseudocholinesterase).

- N.B: Genetic variants in which plasma pseudocholinesterase levels are

low or absent lead to prolonged neuromuscular paralysis.

Mechanism of

action

There are two phases to the blocking effect of Succinylcholine.

* Phase I (initial stimulation)

- Opening of the Na channel associated with the nicotinic receptors

depolarization of the receptor

- transient twitching of the muscle (fasciculations). Mechanism

* Phase II (prolonged inhibition)

- During continuous depolarization:

→ Receptor desensitization.

→ Na+ channel blocked .

→ Paralysis (flaccid paralysis).

Pharmacological

Action

- Produce muscle fasciculation followed by flaccid paralysis.

- Ganglion stimulation, slight histamine release and M2 receptors

stimulation.

Therapeutic Uses Because of its rapid onset of action used in:

1) Endotracheal intubation. 2) Electro-convulsion therapy (ECT).

Side

Effects

1: Prolonged Apnea:

- Apnea; is a term for suspension of external breathing.

- Administration of Succinylcholine to a patient who is deficient in plasma

cholinesterase or who has an atypical form of the enzyme can lead to

prolonged apnea → paralysis of the diaphragm.

2: Bradycardia: (can be overcome by administration of Atropine)

- Due to ganglionic stimulation and cardiac M2 receptors stimulation.

3: Post-operative muscle pain (Myalgias): Due to initial fasciculation.

4: Increase IOP :

- Due to contraction of extra-ocular muscle applying pressure to the eye

ball.

5: Hyperkalemia:

- Patients with burns, nerve damage or neuromuscular disease, closed

head injury and other trauma can respond to Succinylcholine by releasing

K+ into the blood → may cause cardiac arrest (rare).

- Temporary treatment:

• Regular insulin: Which K+ concentration in plasma (enhance entry

of K+ and prevent it is efflux from the tissues). Dose: IV injection

of 10-15 units of regular insulin along with 50 ml of 50% dextrose

to prevent hypoglycemia.

• Salbutamol (B2-selective agonist): This drug also decrease blood

levels of K+ by promoting its movement into cells. Is administered

by nebulizer (10-20 mg).

6: Malignant Hyperthermia (MH):

- Is a rare life-threatening condition that is usually occurs in susceptible

patients, expesure to halogenated hydrocarbon anesthetics (e.g.

Halothane) and neuromuscular blocker succinylcholine→ (Rabid ↑ in

muscle metabolism).

- Characterized by:

▪ Very high temperature and unexplained tachycardia.

▪ Muscle rigidity due to → increase muscle contraction and

intensive pain → due to abnormal increase of Ca2+ from

sarcoplasmic reticulum.

▪ Metabolic acidosis (the body produces excessive quantities of

acid or kidneys are not removing enough acid from the body).

- Treatment by:

- Cooling patient.

- Dantrolene (Direct skeletal muscle relaxant) Prevent release of Ca2+

from sarcoplasmic reticulum.

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