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DEFINITIONS OF MUSCLE RELAXANTS


Muscle relaxants are drugs that either act peripherally

on N.M junction/skeletal muscle fibers or centrally in the cerebrospinal axis to reduce skeletal muscle tone. OR Muscle relaxants are anesthetic adjuncts administered to improve relaxation of skeletal muscles during surgical or diagnostic procedures.

NEUROMUSCULAR BLOCKING AGENTS(NMBA)


NMBA are the drugs that produce their affects by

actions at the neuromuscular junction. OR Neuromuscular blocking drugs are the agents that interfere with the transmission of nerve impulses from the somatic nerve endings to the skeletal muscle fibers and produce profound muscle relaxation.

CLASSIFICATION OF MUSCLE RELAXANTS


ON THE BASIS OF SITE OF ACTION:
A)PERIPHERALLY ACTING MUSCLE RELAXANTS:

a)Neuromuscular blocking drugs:


- COMPETITIVE/NON DEPOLARISING N.M.BLOCKING DRUGS

-NON COMPETITIVE/DEPOLARISING N.M BLOCKING DRUGS

COMPETITIVE/NON DEPOLARISING N.M.BLOCKING DRUGS


LONG ACTING DRUGS:

EXAMPLES: - d-tubocurarine -pancuronium -Gallamine -doxacurium

INTERMEDIATE ACTING DRUGS:

EXAMPLES: -vancuronium -rocuronium -atacurium SHORT ACTING DRUGS: EXAMPLE: -mivacurium

NON COMPETITIVE/DEPOLARISING N.M BLOCKING DRUGS


EXAMPLES:
-suxamethonium (succinylcholine) -decamethonium

b)Directly acting drugs:


Examples: -Dantrolene -quinine

B)CENTRALLY ACTING MUSCLE RELAXANTS


GLYCERAL ETHER:

EX -guaiphenesin -mephenesin CARBAMATE DERIVATIVE: EX -methocarbamol GABA DERIVATIVES: EX -baclofen

MECHANISM OF SK.MUSCLE CONTRACTION

Initiation of impulse Release of acetylcholine

Activation of nicotinic receptors at motor end plate


Opening of ion channels, passage of Na+ ion,

depolarization of motor end plate Muscle contraction Neuromuscular blocking drugs used in clinical practice, interfere this process.

Drugs can block neuromuscular transmission/ or muscle contraction by acting: PRESYNAPTICALLY to inhibit synthesis and release of acetylcholine(practically not used) As they may have whole body unspecific nicotinic as well as muscrinic affects POSTSYNAPTICALLY .to block receptor activity .to block ion channel at end plate.

Clinically these drugs are only used as an adjuvant to general anesthesia, (only when artificial respiration is available) They interfere with the post synaptic action of Acetylcholine NON DEPOLIZING AGENTS(Majority) Act by blocking Ach receptors,(in high doses)act by blocking ion channels. DEPLARIZING AGENTS: Act as agonists at Ach receptors

MECHANISM OF ACTION
NONDEPOLARIZING AGENTS
a)AT LOW DOSES: These drugs combine with nicotinic receptors and prevent Ach binding as they compete with Ach for receptor binding, so they are called competitive blockers. Thus prevent depolarization at end plate. Hence inhibit muscle contraction so relaxation of skeletal muscle occurs.

Their action can be overcome by increasing conc. of

Ach in synaptic gap(by inhibiting acetylcholinesterase Enzyme) Examlples: Neostigmine,physostigmine,edrophonium Anesthetists use this strategy to shorten the duration of blockage or overcome the overdosage.

At High doses:
These drugs block ion channel of the motor end plate Leads to further weakening of the transmission and

reduce the ability of Acetylcholinesterase inhibitors to reverse the action.

ACTIONS
All the muscles are not equally sensitive to blockade.
Small and rapidly contracting muscles are paralyzed

first.
Respiratory muscles are last to be affected and first to

recover

PANCURONIUM
This was the first in series of nondepolarizing NMBA having a steroid nucleus with corticoid activity. 5time more potent than d,tubocurarine Quick onset of action No ganglion blocking activity,No histamine release No change in BP No effect on CNS Reversed by anticholinesterase Metaboloized in liver,excreted in urine

VECURONIUM
Slightly more potent than pancuronium but duration of action is about half of pancuronium
Not cause histamine release,Nm ganglion blockade,vagolylic action hence cause minimal cardiovascular affect Metabolized by hepatic microsomal enzymes and excreted in bile Good muscle relaxant having cardiovascular stability

DEPOLARIZING AGENTS
DRUGS: Suxamethonium(succinylcholine) Decamethonium

MECHANISM OF ACTION These drugs act like Ach but persisit at the synapse at high conc. and for longer duration and constantly stimulate the receptors. First opening of Na+ chanel occurs resulting in depolarization,this leads to transient twitching of muscles,continued binding of drugs make the receptors incapable to transmit the impulse,paralysis occurs. The continued depolarization makes the receptors desensitized and causes flaccid paralysis.

THERAPEUTIC USES:
When rapid endotracheal intubation is required(rapid

action is essential to prevent gastric aspiration) Electroconvulsive shock therapy PHARMACOKINETICS: Administered intravenously. Due to rapid inactivation by plasma cholinesterase, given by continued infusion.

SUCCINYLCHOLINE
Succinylcholine is the only depolarizing muscle

relaxant in use today. After I.V injection affect can be seen in 15 sec Duration of action varies in species e.g3 min in pigs,30 min in dogs,15-30 min human. It causes paralysis without appreciable ganglion blocking activity. Produces transient twitching of sk.muscles before causing block

SUCCINYLCHOLINE
It causes maintained depolarization at the end

plate,which leads to loss of electrical excitability. It has shorter duration of action. It stimulate both sympathetic and parasympathetic ganglion. In low doses it produces negative inotropic and chronotropic effect In high doses produces positive inotropic and chronotrpic affect.

SUCCINYLCHOLINE
It acts like Ach but diffuses slowly to the end plate and

remain there for long enough that the depolarization causes electrical excitability& produces hyperkalaemia. If cholinesterase is inhibited,it is posible for circulating Ach to reach a level sufficient to cause depolarization.

UNWANTED EFFECTS
Bradycardia, prevented by atropine
Hyperkalemia in patients with trauma or burns May cause dysrythmia or even cardiac arrest Inc.intraocular pressure due to contracture of extra

ocular muscles. Inc. intragastric pressure which may lead to emesis or aspiration of gastric contents.

UNWANTED EFFECTS
Apnea

Administration of drug to a patient wth deficient cholinesterase enzyme may lead to prolonged apnea due to paralysis of diaphragm. Hyperthermia Occasionally when drug is administered with helothene,melignant hyperthermia may occur.

CONTRAINDICATIONS:
Sever liver disease
Sever burns Massive tauma Patients having typical psuedocholinesterase Pt. having penetrating wounds of eyes Malnutrition,sever anemia Uremia

DRUG INTERACTIONS
Drugs that inhibit N.m transmission like

AG,quinidine,calcium channel blockers,local anesthetics & Mg can potentiate the affects of suxamethonium. Drugs like neostigmine & OP that inhibit cholinesterase may prolong duration of action of suxamethonium. Diuretics may increase their effect

PROPERTIES OF N.M BLOCKERS


DRUG ELEMINATION VIA
Plasma AchE Plasma AchE

DURATION OF ACTION
5-10 min 10-20min

Short Acting
Succinylcholine Mivacurium

Intermediate acting
Atracurium Vecuronium Rocuronium Spontaneus Hepatic and renal Hepatic and renal 20-35min 20-35min 20-35min

Long acting
Pancuronium Renal 60min

DANTROLENE
It acts directly

It reduces sk.muscle strength by interfering with

excitation contraction coupling into muscle fiber by inhibiting the release of activating calcium from sarcoplamic stores. Very useful in the treatment of melignant hyperthermia caused by depolarizing muscle relaxants. Can be given orally or by I.V,oral absorption is 1/3 Half life of drug is 8-9hrs

DANTROLENE SODIUM
(DANTRIUM)
SIDE EFFECTS: Muscle weakness,sedation,rare

hepatitis. USES:Cerebral palsy,multiple sclerosis,Melignant hyperthermia,tratment of procine stress syndrome.in the treatment of functional urethral obstruction in cats and dogs(in west).

BACLOFEN
CENTRALLY ACTING MS.RELAXANT
It acts through GABA-B receptors
It causes hyperpolarization by inc. K+ condutance

,reducing Ca++ influx and redduces excitatory transmitter in brain as well as spinal cord. It also reduces pain by inhibitry substance P in spinal cord It is less sedative

BACLOFEN
It is rapidly and completely absorbed orally
It has half life of 3-4hrs It may increases seizures in epileptics It is also useful to prevent migrain

THERAPEUTIC USES OF NMBA


Endotracheal intubation i.e suxamethonium In crush injuries of chest to provide rest to respiratory muscles. In ECT to shock therapy to prevent trauma In the diagnosis of Mysthenia Gravis but it may be dangerous For the treatment of poisoning due to convulsant drugs e.g strychnine For the treatment of tetanus and tetanus epilepticus

CLINICAL PROBLEMS ASSOCIATED WITH NMBA


Potentiated by inhaled anesthetics(isoflurane)
Potentiated by Aminoglycoside and calcium channel

blockers Can block autonomic ganglia at higher doses Respiratory paralysis

FACTORS AFFECTING NEUROMUSCULAR BLOCKADE


1) IMPAIRED METABOLISM AND EXCRETION The effect may increase by dec metabolism especially when drugs dependent on hepatic biotransformation and renal excretion (gallamine,pancuronium,doxacurium) 2) ANESTHETIC DRUGS INHALANT anesthetic agent cause a time and dose dependent enhancement of the intensity and duration of block produced by muscle relaxant

The order of potency of some the inhalation anesthetics in enhancing muscle relaxant effect is as follows: Diethyl Ether>Enflurane>Isoflurane>Desflurane >Halothan. 3) ACID-BASE DISTURBANCES Respiratory Acidosis.increases Nm blockade Respiratory Alklosis..decreases the effect

4) ELECTROLYTE DISTURBANCES
Alteration in serum concentration of K,Ca,Mg

influence neuromuscular blockade POTASSIUM Hypokalemia result in hyperpolarization of end plate and resistant to Ach induced depolarization. Hyperkalemia lowers the resting membrane potential,opposing the effect of muscle relaxant

CALCIUM
Hypocalcaemia decrease Ach release,muscle action

potential,and muscle contraction strength thus increasing the effect NM blockade Hypercalcemia decreases the effect of d.tubocurarine,pancuronium,other NMBA. MAGNESIUM It increases the duration of action of NMBA

5) HYPOTHERMIA
Slows drug elemination & decreases nerve conduction

and muscle contraction. So in hypothermia,muscle relaxant dose may need to be reduced to prevent prolong paralysis.

6) AGE
Receptor immaturaty&decreased clearance appears to inc the potency of muscle relaxants in young.

7) NEUROMUSCULAR DISORDERS
Animals with NM disorders may exhibit unpredictable

responses to both depolarizing and nondepolarizing muscle relaxants. 8) ANTIMICROBIAL & OTHER DRUGS INTERACTION

POLYMIXENS- may depress postsynaptic sensitivity to Ach & enhance channel block. AMINOGLYCOSIDE-have presynaptic site of action to depress Ach release.

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