2. Drugs acting on Autonomic nervous system

Skeletal Muscle Relaxants

Skeletal muscle relaxants are used in various surgical procedures during anesthesia, because they decrease spasm and spasticity.


Classified into three groups

  1. Peripheral acting
  1.   Centrally acting
  2.   Locally / Directly acting

Peripherally and centrally acting drugs are also known as indirectly acting drugs.

Peripherally acting:

Non Depolarizing Neuromuscular Blockers:

(Act at NMJ/ Most commonly used/ Also called NM blocking agents/ antagonists)

1. Isoquinoline Derivatives:





Mivacurium (shortest duration of action/slow onset/increase histamine release thus cause flushing, bronchospasm)




2.  Steroid Derivatives

Panuronium (can cause moderate increase in heart rate and small increase in cardiac output but no effect on TPR, because:

  1. Vagolytic action
  2. Release of NE by nerve endings
  3. Blockage of reuptake of NE)


Rapacuronium (short acting, now withdrawn)

Procuronium (fastest acting within 60-120 seconds, hence used for tracheal intubation)


Procuronium and Vecuronium are intermediate acting. Panuronium and Pipecuronium are long acting.

Depolarizing Neuromuscular Blockers (agonists)




Centrally acting

(Act on CNS)


Diazepam, clonazepam, Nitrazepam

GABA Analogues



Propanediol Derivatives


Miscellaneous Compounds





Directly Acting:

(Act directly on muscles)


Neuromuscular Junction

Motor end plate is a specialized area where there is junction of the nerve fiber with the muscle fiber. There is unusual distribution of ions in the muscle fiber:

There is more negative charge inside the membrane in the resting phase.

On arrival of the action potential, release of acetyl choline from nerve terminals occurs, which binds to post-synaptic nicotinic receptors. Stimulation of these receptors cause increased influx of Na+ ions, which leads to depolarization and contraction.

Fate of acetyl choline is that it is hydrolyzed by acetylcholine esterase.

Directly acting NM blocking agents do not interfere with the release of acetyl choline. They only interact with post-synaptic nicotinic receptors.

Botulinum Toxin A

Botulinum toxin A interferes with the release of acetyl choline. It is produced by anaerobic bacteria ‘Clostridium botulinum’. It occurs due to food poisoning and can lead to respiratory paralysis and even death of the patient. However, this is used therapeutically against bronchospasm in athletes, because of the repeated use of the limbs, there is damage to the wrist and knee joints and this toxin relaxes the muscles. It is given IM and effects start within a few days. They remain for a few months. Toxin can be repeated if required.

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Tubocurarine -Non Depolarizing Neuromuscular Blocker

Suxamethonium -Depolarizing Neuromuscular Blocker

Factors affecting actions of Neuromuscular blockers

Benzodiazepines as Centrally Acting Skeletal Muscle Relaxants

Baclofen and Progabide -GABA Analogues

Mephenesin and Meprobamate -Propandiol Derivatives

Cyclobenzaprine, Orphenadrine and Tizanidine

Tubocurarine -Non-depolarizing Neuromuscular Blocker

Tubocurarine is a non-depolarizing neuromuscular blocker. Non-depolarizing neuromuscular blockers interfere with the NM transmission. D-tubocurarine is a natural substance, obtained from curare, which was used in ancient times as an arrow head poison to kill animals. Source of curare is ‘Chondrodendron Tomentosum’ and Strychnas.


It is a quaternary compound.

Mechanism of Action:

It competes with acetylcholine for post-synaptic nicotinic NM receptors and blocks them.

No flow of ions occurs, thus there is no contraction.

This blockage is competitive and reversible, the sequence of events for this blockage are:

1. Muscles capable of rapid movements like fingers, toes, eyes and jaw muscles are the first to go.

2. Muscles of neck, limbs and trunk are second to go.

3. Respiratory muscles, intercostal muscles and diaphragm at last. (Diaphragm paralyzes last and is the first to recover)

The recovery occurs in the opposite manner.

Pharmacological Actions:

  1. Release of histamine (premedication with antihistaminics is useful, otherwise hypotension might occur)
  2. Causes weak blockage of ganglion
  3. Blocks adrenal medulla

Over dosage:

The effect of this drug can be antagonized by anticholine esterases e.g. neostigmine given in a dose of 1-2 mg I/V. Neostigmine is combined with atropine to block muscarinic effects.

Atropine has biphasic effect on heart, gives first bradycardia then tachycardia, so given shortly before neostigmine to prevent activation of cardiac muscarinic receptors.


Cannot of given orally is quaternary compound. If given orally, no absorption occurs. By I/V it is excreted as such in urine. Onset of action is 4-5 minutes. Duration of action is 30-60 minutes. Short duration is due to redistribution and not due to diminution. That is why it should not be given repeatedly; otherwise it will accumulate in fat tissue and cause toxicity.

Therapeutic Uses

  1. Skeletal muscle relaxant for endotracheal intubation.
  2. When this drug is used with general anesthetics, lesser dose of general anesthetics is required.
  3. Used in chest crush injuries to relax chest muscle.
  4. Given in convulsions
  5. Is an antidote for strychnine poisoning

Adverse Effects

  1. Hypotension (because of histamine release and ganglion blockage, vasodilatation)
  2. Bronchospasm (histamine release)
  3. Rash (histamine)
  4. Vomiting (paralysis of sphincters and diplopia can be there due to paralysis of muscles)


  1. Respiratory insufficiency –emphysema, bronchial asthma
  2. Renal disease


5-15 or 20 mg dose are available.

Dose should not exceed 400 mg.

Atracurium, Cisatracurium, Gallamine and Steroid Derivatives -Non Depolarizing Neuromuscular Blockers


Actions are similar to those of d-tubocurarine. It is safer and more potent than d-tubocurarine because

  1. It is eliminated through Hoffmann elimination
  2. It is safer to be used in patients with renal and hepatic diseases
  3. No histamine is released and no ganglion blockage and tachycardia is observed (can cause hypotension due to systemic histamine release)

Atracurium is broken down into ludanosine and quaternary acid.

Duration of action is 30-35 minutes.


Cisatracurium is an analogue of atracurium (stereoisomer). It is more potent and safer than d-tubocurarine. Actions are similar to atracurium.


Gallamine is a synthetic drug. It is less potent as compared to d-tubocurarine. It can cause ganglion blockage, histamine release and sometimes tachycardia.

Steroid derivatives:

Steroid derivative are synthetic drugs. They are 5 times more potent than d-tubocurarine.

No histamine is released, no ganglion blockage occurs. Tachycardia is sometimes present.

Suxamethonium -Depolarizing Neuromuscular Blocker:

Suxamethonium is the only drug used in the category of depolarizing neuromuscular blockers and is synthetic, consisting of 2 molecules of acetyl choline joined together.

Mechanism of Action

It binds to post-synaptic nicotinic receptors, activating them and opening ion channels, which causes depolarization and contraction.

Phase I Block

In contrast to acetyl choline, which is hydrolyzed in synaptic cleft, this suxamethonium is not rapidly metabolized. It remains attached to receptors for longer durations, leading to persistent depolarization of receptors. Muscle membrane becomes irresponsible to further stimulus and this is known as phase I block or depolarizing block. Small contractions of the muscle fibers and fasciculations are seen in this phase.

Phase II Block

After some time, the muscle membrane becomes desensitized to the effects of neurotransmitters, this is known as phase II block or the desensitizing block. In this phase, flaccid paralysis of the muscles is seen.

Over dosage

The effects of this drug cannot be antagonized by anti choline esterases.

Ventilatory support and supportive management is required as there is no antidote.

If injections are repeated within 5-10 minutes, severe bradycardia occurs, leading to cardiac arrest. Atropine is then given in a dose of 1.5 mg to prevent cardiac arrest. Reason of bradycardia is:

  1. Direct myocardial effects
  2. Increased muscarinic stimulation
  3. Increased ganglionic stimulation

Stimulates Muscarinic & Nicotinic receptors:

This drug stimulates both nicotinic and muscarinic receptors;

  1. In low doses, negative ionotropic and chronotropic effects
  2. In high doses, positive ionotropic and chronotropic effects


Given by I/V route.

Has rapid onset (in one minute)

Duration of action is 5-10 minutes (short) due to degradation by enzyme psudocholine esterase, metabolized into choline and succinic acid. (Succinyl choline broken into succinomonocholine, which gives choline and succinic acid)

Certain local anesthetics like procaine are also metabolized by pseudocholine esterase, which can potentiate the effects of succinyl choline (suxamethonium) when given together.

Therapeutic Uses:

  1. For short surgical procedures (abdominal surgeries)
  2. Bronchoscopy
  3. Laryngeoscopy
  4. Esophagoscopy
  5. Can be used in electroconvulsive therapies to prevent convulsions and trauma e.g. status epilepticus
  6. Also used in orthopedic manipulations

Adverse Effects

  1. In patients with atypical pseudocholine esterases, suxamethonium is not metabolized, leading to prolonged respiratory paralysis and apnea. This may occur in liver disease or genetically atypical enzyme.
  2. Can produce bradycardia if given for a prolonged period of time repeatedly.
  3. Muscle pain may occur due to fasciculations (unsynchronized contractions of adjacent muscle fibers before paralysis)
  4. Malignant hyperpyrexia, an idiosyncratic response. There is hyperthermia, hyertonia and hyperpyrexia along with hyperkalemia
  5. Can lead to increased intragastric pressure (5-40 cm H2O) and can produce vomiting, aspiration pneumonia. Thus should be given on empty stomach. Following are more prone:
    a. Diabetics having delayed gastric emptying
    b. Trauma
    c. Obesity
    d. Esophageal dysfunction
  6. Can increase intraocular pressure, due to contraction of intraocular muscles during phase I block or due to dilatation of intraocular choroidal blood vessels.
  7. Hyperkalemia due to muscle damage, dangerous in patients predisposed to hyperkalemia like patients with wounds, trauma and peritoneal infections. It might lead to cardiac arrest.


  1. Hyperkalemia
  2. Atypical pseudocholine esterases
  3. Liver diseases
  4. Increased intraocular pressure as in glaucoma

Drug Interactions

Metabolized by pseudocholine esterase, all of drugs metabolized by same enzyme potentiate each other’s effects. Local anesthetics can potentiate the effects of suxamethonium e.g. Procaine or lidocaine can potentiate the effects.


Starting dose is 10 mg, which may be increased to 100 mg.

Factors affecting actions of Neuromuscular blockers:

Several factors influence the action of neuromuscular blockers, these include:

1. Blood flow to muscles

If blood flow is rapid, onset of action is rapid and duration of action is short.

2. Temperature

Hyperthermia potentiates the effects of non-depolarizing neuromuscular blockers, while hypothermia potentiates the effects of depolarizing neuromuscular blockers.

3. pH

Acidosis potentiates the effects of non-depolarizing neuromuscular blockers.

4. Potassium concentration

Hyperkalemia potentiates the effects of depolarizing neuromuscular blockers. Hypokalemia potentiates the effects of non-depolarizing neuromuscular blockers.

5. Antibiotics

Antibiotics like amino glycosides, streptomycin, decrease the release of acetylcholine at nerve terminals and thus potentiate the effects of non-depolarizing neuromuscular blockers.

6. Atypical Pseudo cholinesterase

Suxamethonium is metabolized by pseudo cholinesterase. If there is deficiency or presence of atypical pseudo cholinesterase, it might lead to respiratory paralysis or apnea.

7. Anti-arrhythmic drugs

Drugs like quinidine have curare like actions causing relaxation of muscles. They potentiate the effects of non-depolarizing neuromuscular blockers.

8. Myasthenia gravis

In myasthenia gravis, peripherally acting neuromuscular blockers are not administered.

9. Renal/ liver diseases

Care must be taken as Rapacuronium and Vecuronium are metabolized by the liver.

d-Tubocurarine and Metocurium are eliminated through the kidneys.

10. Calcium channel blockers

Calcium channel blockers potentiate the effects of depolarizing neuromuscular blockers and non-depolarizing neuromuscular blockers.

11. Diuretics

Thiazide diuretics produce hypokalemia, which potentiates the effects of non-depolarizing neuromuscular blockers.

Benzodiazepines as Centrally Acting Skeletal Muscle Relaxants:

Centrally acting muscle relaxants


They produce effects centrally in brain or spinal cord.

Decrease spasm

They are used to decrease the spasm and release spasticity as well as to reduce the pain.

Reasons for spasm

Spasm may be due to:

1. hyperactive stretch reflexes or

2.  increased activation of alpha motor neurons or

3. imbalance between excitatory and inhibitory neurotransmitters.


  1. Multiple sclerosis
  2. Cerebral palsy
  3. CVA

These drugs do not improve the power or functions of muscles; rather actually decrease the power of muscles.

Skeletal muscle relaxants

In patients of stroke, spasticity is important because it helps in walking, providing support. When skeletal muscle relaxants are given, they expose the weakness of limbs.

Mechanism of Action of centrally acting drugs

Decrease the hyperactivity of stretch reflex arc, as well as decrease the activation of alpha motor neurons.

This is achieved either by increasing the release of inhibitory neurotransmitters or decreasing the release of excitatory neurotransmitters. The pain encountered in these spasms is due to release of subs P, which is decreased by these drugs.

These drugs depress the pulse transmission in polysynaptic pathways.


Benzodiazepines are commonly used for relieving skeletal muscle spasms. They are safe as have fewer adverse effects.

Mechanism of Action

They produce their effects by GABAergic effect meaning that they potentiate the effects of GABA, without directly activating GABA receptors. They bind GABA A component of supramolecular complex.


They can be given orally or parentally. They can be given I/V for controlling the convulsions in status epilepticus, as well as in tetanus. They are metabolized by the liver.

Adverse effects

Mainly affect CNS, evident in the form of sedation, drowsiness, ataxia, impaired judgment. Only in increased doses can cause depression of CVS and respiratory system.


Given in a dose of 5 mg, which may be increased to 60 mg.

Clonazepam and Nitrazepam have similar actions to that of diazepam, but have shorter duration of action.

Baclofen and Progabide -GABA Analogues:


Baclofen acts as agonist at GABA receptors especially GABA B receptors. Ultimately there is hyper polarization due to:

  1. Increased potassium conductance
  2. Decreased release of excitatory neurotransmitters
  3. Decreased release of subs P


  1. Musculoskeletal disorders
  2. Neuralgia
  3. Muscle spasms

Adverse effects

  1. Confusion
  2. Sedation
  3. Drowsiness
  4. Weakness
  5. Fatigue
  6. Hypotonia


Psychiatric illness


Dose is 15 mg, which can be increased to 100 mg.


Progabide is a less commonly used muscle relaxant acting at both GABA A and GABA B receptors. It produces muscle relaxant effects because of active metabolite.

Mephenesin and Meprobamate -Propandiol Derivatives


Mephenesin acts by decreasing the transmission in polysynaptic pathway. It produces muscle relaxant effects. It can be used in:

1. Strychnine over dosage

2. Convulsions

Adverse effects include sedation and drowsiness.

Dose is 1-3 grams daily in divided doses.


Meprobamate is less commonly used because of strong sedative effects which hinders normal activities of individual. It is an enzyme inducer and can interact with various drugs.

It is contraindicated in porphyria.

Cyclobenzaprine, Orphenadrine and Tizanidine


It mainly acts at the level of brainstem. It has anticholinergic effect and is a good muscle relaxant. It is given orally and is metabolized by the liver.

It is usually given in combination with Methacarbamol (same group).

It is used in adjuvant therapy and in physiotherapy with other drugs.


Orphenadrine has anticholinergic activity. It has muscle relaxant effects and can be used in strychnine over dosage. However, it produces sedation, drowsiness and confusion.


Tizanidine is a newer drug. It is a congener of Clonidine, which is antihypertensive drug. It acts as agonist at alpha 2 receptors and enhances pre and post synaptic inhibition.

It can be given orally but bioavailability is less because of extensive first pass metabolism. It is beneficial in patients on bed rest. Main adverse effects are similar to those of orphendadrine.

Dantrolene -Directly Acting Skeletal Muscle Relaxant:


Chemically dantrolene is hydantoin derivative.

Mechanism of Action

It decreases the release of calcium from sarcoplasmic reticulum by binding to special type of calcium receptors, known as Ryanidine receptors. Because of blockage, there is decrease in release of calcium and decrease in spasm.

It has no effects on smooth muscles and cardiac muscles.


It is given orally and has delayed onset of action. Half life is 8-15 hours. It is metabolized in the liver and is eliminated in bile and urine.

Therapeutic uses

Main use is in malignant hyperthermia, an idiosyncratic response seen with general anesthetics.

Besides dantrolene, bromocriptine may be given along with sponging for decreasing temperature.

Adverse effects

  1. Hypotonia
  2. Muscle weakness
  3. Drowsiness
  4. Sedation


Given carefully in renal/hepatic diseases. Starting dose is 25 mg, which may be increased to 100 mg.

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