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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.
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.
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.
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
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
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
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
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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