Skeletal Muscle Relaxants

By: Aditya Arya

A Muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: 

Neuromuscular blockers and Spasmolytics. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate and have no CNS activity. They are often used during surgical procedures and in intensive care and emergency medicine to cause paralysis.

Spasmolytics, also known as

Centrally-acting muscle relaxants:

Are used to alleviate musculoskeletal pain and spasms and to reduce spasticity in a variety of neurological conditions. While both neuromuscular blockers and spasmolytics are often grouped together as muscle relaxants.

History of Neuromuscular blocking agents

• Early 1800’s – curare discovered in use by South American Indians as arrow poison

• 1932 – West employed curare in patients with tetanus and spastic disorders

• 1942 – curare used for muscular relaxation in general anesthesia

• 1949 – gallamine discovered as a substitute for curare

• 1964 – more potent drug pancuronium synthesized

Uses of neuromuscular blocking agents

• By intravenous or systemic administration:– Adjuvant in surgical anesthesia to obtain

relaxation of skeletal muscle– “Balanced” anesthesia – to minimize anesthetic

use without compromising analgesia– To assist in intubation (esp. succinylcholine)– Corneal or retinal surgeries to obtain relaxation

of extraocular muscles (cisatracurium)– Therapy of spastic disorders

Neuromuscular blocking drugs :

Block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles.

This is accomplished either by acting presynaptically  via the inhibition of acetylcholine (ACh) synthesis or release, or by acting postsynaptically at the acetylcholine receptors of the motor nerve end-plate.

While there are drugs that act presynaptically (such as botulinu toxin and tetrodotoxin), the clinically-relevant drugs work postsynaptically.

Clinically, neuromuscular block is used adjunctively to anesthesia to produce paralysis, so that surgery, especially intra-abdominal and intra-thoracic surgeries, can be conducted with fewer complications.

Because the appropriate dose of neuromuscular blocking drug may paralyze muscles required for breathing (i.e. the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

These drugs fall into two groups:

Non-depolarizing blocking agents: These agents constitute the majority of the clinically-relevant neuromuscular blockers. They act by competitively blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors.

Depolarizing blocking agents: These agents act by depolarizing the plasma membrane of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

Steps in neuromuscular transmission

Connective Tissue

Covering Skeletal Muscle

Microstructure of Skeletal

Muscle

Within the Sarcoplasm

Neuromuscular Junction

Actin & Myosin Relationship

Classes of neuromuscular blocking agents

• Competitive (non-depolarizing) neuromuscular blocking agents

• (prototype: d-tubocurarine/curare)

• Depolarizing neuromuscular blocking agents

• (prototype: succinylcholine)

Non-depolarizing blocking agents:A neuromuscular nondepolarizing agent is a form of neuromuscular blocker which do not depolarize the motor end plate.

Tubocurarine:

Found in curare of the South American plant Pareira, Chonodendron tomentosum, is the prototypical non-depolarizing neuromuscular blocker.

It has a slow onset (>5 min) and a long duration of action (1–2 hours).

Side effects include hypotension.

 It is excreted in the urine.

Competitive neuromuscular blocking agents

• d-tobocurarine

• Gallamine (Flaxedil)

• Alcuronium (Alloferin)

• Pancuronium (Pavulon)

• Atracurium (Tracrium)

• Cisatracurium (Nimbex)

• Vecuronium (Noncuron)

• Doxacurium (Neuromax)

Blue = greatest veterinary use

Neuromuscular blockers

Non depolarizing agents

Isoquinoline derivatives steroid derivatives– Tubocurarine Pancuronu ium– Doxacurium Pipecuronium– Atracurium Rapacuronium– Metocurine Rocuronium– Mivacurium Vecuronium

• Depolarizing agents– Suxamethonium (Succinylcholine)– Decamethonium

Competitive neuromuscular blocking agents

• d-tubocurarine : slight hypotension; histamine (HA) release (problem in asthma); limited use.

• Gallamine triethiodide : tachycardia; • no HA release; crosses placental barrier.

• Alcuronium chloride : similar to curare, • shorter lasting; slight hypotension and tachycardia.

• Pancuronium bromide : long-acting; • slight tachycardia and hypertension.

Atracurium besylate :

Intermediate-acting

safe in liver and kidney disease; bradycardia may result during surgical manipulations, esp ophthal-mologic, ENT, or laparoscopy (treat with atropine or glycopyrrolate);

precipitates in alkaline pH; can cause HA release at higher doses.

Probably most used in veterinary medicine.

• Cisatracurium besylate:• one of 10 isomers of atracurium; 3X potency;

immediate onset of action; used in ophthalmologic surgeries.

• Vecuronium bromide : • intermediate-acting; lack of CV or HA-releasing

effects; drug of choice when CV stability required

• Doxacurium chloride : • long-lasting, most potent agent known; minimal

CV or HA-releasing effects;

Adverse Effects

• Main adverse effect is drowsiness

• Muscle relaxants are known to be addictive

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Effect of competitive blocking agents on skeletal

muscle

• First: motor weakness• Then flaccid motor

paralysis

• Sequence of paralysis– Small, rapidly moving

muscles first– Then large muscle

masses– Then toes, jaw, eyes,

ears, limbs, neck and trunk.

– Finally, intercostal muscles and diaphragm paralyzed

Competitive blockade reversed by neostigmine

(Ns)

Effect of competitive blockers on cardiovascular

system

• Decreased blood pressure : due to histamine release

• Increased heart rate (baroreceptor reflex)

Pharmacokinetics:

• Onset of action - slow• Duration of action -

short initially, with residual effect

• (Cumulative with repeated doses)

• Poorly absorbed from GI tract

• Termination of action: hepatic metabolism/ renal excretion.

• Accumulation may occur in patients with renal insufficiency

• Action enhanced or potentiated by:– Acidosis

– Aminoglycoside antibiotics (inhibition of ACh release…membrane stabilization)

– Volatile anesthetics (membrane stabilizers)

• Action antagonized :

By cholinesterase inhibitors (neostigmine, edrophonium), tetanic stimulation

Coagulability of blood decreased (due to release of heparin from mast cells)

• Undesirable effects :

histamine release, cardiovascular effects

• Therapeutic advantages :

no fasciculation, no CNS effects

Depolarizing blocking agents:

A neuromuscular depolarizing agent is a form of neuromuscular blocker which depolarize the motor end plate. An example is succinylcholine.Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine.

This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.

There are two phases to the depolarizing block. During phase I (depolarizing phase), they cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons.

At this point, full neuromuscular block has been achieved

Depolarizing neuromuscular blocking agents

• Succinylcholine (suxamethonium )

• Rocuronium

• Mivacurium

Suxamethonium : ( succinylecholine)• Mechanism of action:

• These drugs act like acetylcholine but persist at the synapse at high concentration and for longer duration and constantly stimulate the receptor.

• First, opening of the Na+ channel occurs resulting in depolarization, this leads to transient twitching of the muscle, continued binding of drugs make the receptor incapable to transmit the impulses, paralysis occurs.

• The continued depolarization makes the receptor incapable of transmitting further impulses.

Therapeutic uses:• When rapid endotracheal intubations is

required.

• Electroconvulsive shock therapy.

Pharmacokinetics:• Administered intravenously.

• Due to rapid inactivation by plasma cholinestrase, given by continued infusion.

Succinylcholine:• It causes paralysis of skeletal muscle.• Sequence of paralysis may be different from that of

non depolarizing drugs but respiratory muscles are paralyzed last

• Produces a transient twitching of skeletal muscle before causing block

• It causes maintained depolarization at the end plate, which leads to a loss of electrical excitability.

• It has shorter duration of action.

Depolarizing agents:

Effect on skeletal muscle: • fasciculation, • weakness, • paralysis

• Effect on cardiovascular system:

• increased blood pressure,• increased or decreased

heart rate (due to stimulation of parasympathetic and/or sympathetic ganglia)

Depolarizing agents.

Onset of action :• rapid (1 minute)

Duration of action :• short; • however may revert to

phase II block

• Termination of action:

metabolized by plasma pseudocholinesterase and liver.

• With SCh, initial metabolite is succinylmonocholine, weaker, predominately competitive blocking action.

Action enhanced or potentiated by:

• neostigmine and organophosphates (cholinesterase inhibitors),

• isoflurane.

Undesirable side effects:

• muscle fasciculation,

• hyperkalemia (important in patients with congestive heart failure) Phase II block

Undesirable side effects cont….:• 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 :

• short duration of action,

• little histamine release

THANK YOU

Centrally acting: (spasmolytic drugs)

Centrally Acting Muscles Relaxant:

These are the drugs which reduces skeletal muscles tone by a selective action in the cerbrospinal axis, without altering conciousness. They selectively depress spinal and supraspinal polysynaptic reflexes involved in the regulation of muscle tone without significantly affecting monosynaptically mediated stretch reflex.

Classification:1.Mephenesin Congeners: Mephenesin Carisoprodol Chlorzoxazone Chlormezanone Methocarbamol

Classification:1.Mephenesin Congeners: Mephenesin Carisoprodol Chlorzoxazone Chlormezanone Methocarbamol

2. Benzodiazepines: Diazepam and Others

3. GABA Derivatives : Baclofen

4. Central α2 agonist: Tizanidine

Carisoprodol :

It has a favorable muscle relaxant :Sedative activity ratio with weak analgesic, antipyretic and

anticholinergic actions in addition .

Uses:Musculoskeletal disorders associated with muscle spasm

Chlorzoxazone:

It is pharmacologically similar to mephenesinLonger duration of actionBetter tolerated orally

Chlormezanone :

It has antianxiety and hypnotic as well :Has been used for Tension associated with increased muscle

tone

Methocarbamol:

It is less sedative and longer acting than mephenesinUses:Reflex muscle spasms and Chronic neurological diseases

Used i.v without producing thrombophlebitis and haemolysis:Used for orthopedic procedures and tetanus

Diazepam :

It is a prototype of benzodiazapines which act in the brain on specific receptors enhancing GABAergic transmission :

Uses:It is particularly valuable in spinal injuries and tetanus.Comined with analgesic, it is popular for rheumatic disorders associated with muscle spasm.Baclofen:

This analogue of the inhibitory transmitter GABA acts as a selective GABAB RECEPTOR AGONIST .

GABA Receptors have been divided into :

GABAA receptor: Intrinsic ion channel receptor : increases cl conductance which is blocked by bicuculline facilitated by BZDs

GABAB receptor G protein coupled receptor hyperpolarizes neurones by increasing k conductance and altering Ca 2+ flux

Site of Action:

Act in the spinal cord where it depresses both polysynaptic and monosynaptic reflexes

Absorbed orally and is primarily excreted unchanged in urine with a t1/2 of 3-4 hours.

Side Effects:

DrowsinessMental confusionWeaknessAtaxia

Tizanidine:

• This is a clonidine congener which is a central Alpha 2 adrenergic agonist, which inhibits release of excitatory amino acids in the spinal interneurones.

Centrally acting muscle relaxants (spasmolytics)

• Used in defective neuronal control of muscle activity – in Scottish terriers (Scotty cramp), Dalmatians, and Labs

• Spasms associated with intervertebral disc disease• Spasms associated with tetanus or strychnine

toxicosis• Adjunct to anesthesia for muscle relaxation

(guaifenesin)• Do not abolish voluntary muscle control

Uses of Centrally Acting Muscle Relaxants:

1. Acute muscle spasms

2. Torticollis, Lumbago, Backache, Neuralgias

3. Anxiety and Tension

4. Spastic neurological diseases

5. Tetanus

6. Electroconvulsive therapy

7. Orthopedic manipulation

BLOOD

Anaemia:

Anemia ( meaning lack of blood) is a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood.

However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin deficiency.

The normal level of hemoglobin is generally

different in males and females. For men, anemia is

typically defined as hemoglobin level of less than

13.5 gram/100ml and in women as hemoglobin of

less than 12.0 gram/100ml.

These definitions may vary slightly depending on

the source and the laboratory reference used

What causes anemia• Any process that can disrupt the normal life span

of a red blood cell may cause anemia. Normal life span of a red blood cell is typically around 120 days. Red blood cells are made in the bone marrow.

• Anemia is caused essentially through two basic pathways. Anemia is either caused:

by a decrease in production of red blood cell or hemoglobin, or

by a loss or destruction of blood.

WHO's Hemoglobin thresholds used to define anemia (1 g/dL = 0.6206 mmol/L)

Age or gender group

Hb threshold (g/dl)Hb threshold

(mmol/l)

Children (0.5–5.0 yrs)

11.0 6.8

Children (5–12 yrs) 11.5 7.1

Teens (12–15 yrs) 12.0 7.4

Women, non-pregnant (>15yrs)

12.0 7.4

Women, pregnant 11.0 6.8

Men (>15yrs) 13.0 8.1

Peripheral blood smear microscopy of a patient with iron-deficiency anemia.

Classification:1. Microcytic :

Microcytic anemia is primarily a result of hemoglobin synthesis failure/insufficiency, which could be caused by several etiologies:

• Heme synthesis defect

– Iron deficiency anemia

– Anemia of chronic disease (more commonly presenting as normocytic anemia)

• Globin synthesis defect

– alpha-, and beta-thalassemia

– HbE syndrome

– HbC syndrome

– and various other unstable hemoglobin diseases

• Sideroblastic defect

– Hereditary sideroblastic anemia

– Acquired sideroblastic anemia, including lead toxicity

– Reversible sideroblastic anemia

2. Macrocytic :

• Megaloblastic anemia, the most common cause of macrocytic anemia, is due to a deficiency of either vitamin B12, folic acid (or both). Deficiency in folate and/or vitamin B12 can be due either to inadequate intake or insufficient absorption. Folate deficiency normally does not produce neurological symptoms, while B12 deficiency does.

Pernicious anemia is caused by a lack of intrinsic factor. Intrinsic factor is required to absorb vitamin B12 from food. A lack of intrinsic factor may arise from an autoimmune condition targeting the parietal cells (atrophic gastritis) that produce intrinsic factor or against intrinsic factor itself. These lead to poor absorption of vitamin B12.

Macrocytic anemia can also be caused by removal of the functional portion of the stomach, such as during gastric bypass surgery, leading to reduced vitamin B12/folate absorption.

Therefore one must always be aware of anemia following this procedure.

HypothyroidismAlcoholism commonly causes a macrocytosis, although not specifically anemia. Other types of Liver Disease can also cause macrocytosis.Methotrexate, zidovudine, and other drugs that inhibit DNA replication.Macrocytic anemia can be further divided into "megaloblastic anemia" or "non-megaloblastic macrocytic anemia". The cause of megaloblastic anemia is primarily a failure of DNA synthesis with preserved RNA synthesis, which result in restricted cell division of the progenitor cells. The megaloblastic anemias often present with neutrophil hypersegmentation (6–10 lobes). The non-megaloblastic macrocytic anemias have different etiologies (i.e. there is unimpaired DNA globin synthesis,) which occur, for example in alcoholism.

Normocytic:

Normocytic anemia:

Normocytic anemia occurs when the overall hemoglobin levels are always decreased, but the red blood cell size (Mean corpuscular volume) remains normal. Causes include:Acute blood lossAnemia of chronic diseaseAplastic anemia (bone marrow failure)Hemolytic anemia

Dimorphic:

When two causes of anemia act simultaneously, e.g., macrocytic hypochromic, due to hookworm infestation leading to deficiency of both iron and vitamin B12 or folic acid or following a blood transfusion more than one abnormality of red cell indices may be seen. Evidence for multiple causes appears with an elevated RBC distribution width (RDW), which suggests a wider-than-normal range of red cell sizes.

Heinz body anemia:

Heinz bodies form in the cytoplasm of RBCs and appear like small dark dots under the microscope.

There are many causes of Heinz body anemia, and some forms can be drug induced. It is triggered in cats by eating onionsor acetaminophen  (paracetamol). It can be triggered in dogs by ingesting onions or zinc, and in horses by ingesting dry red maple leaves

Refractory anemia :

Refractory anemia is an anemia which does not respond to treatment.  It is often seen secondary to myelodysplastic syndromes.Iron deficiency anemia may also be refractory as a clinical manifestation of gastrointestinal problems which disrupt iron metabolism