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96 Cards in this Set

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Neuromuscular Blocking Agents:
Nondepolarizing (Competitive) Blockers
Tubocurarine (generic)
Atracurium (Tracrium)
Mivacurium (Mivacron)
Pancuronium (generic, Pavulon)
Rocuronium (Zemuron)
Pipecuronium (Arduan)
Neuromuscular Blocking Agents:Depolarizing Blocker
Succinylcholine (Anectine: others)
Spamolytic Drugs:
Benzodiazepines: Diazepam (Valium)
Baclofen (generic, Lioresal)
Tazanidine (Zanaflex)
Drugs Act Directly at Skeletal Muscle
Dantrolene (Dantrium)
Botulinium Toxin Type A (Botox
Drugs Used For Acute Local Muscle Spasm:
Cyclobenzapine (generic, Flexeril)
Carisoprodol (generic, Soma)
Neuromuscular blocking agents
What are they?
What do they do?
are drugs used during surgical procedures to cause muscle PARALYSIS-- interfere with transmission at the neuromuscular junction WITHOUT CNS activity.
“Curare”
a generic term for various South American arrow poisons discovered centuries ago. Tubocurarine was the active alkaloid in curare; curare was first used for promoting muscle relaxation with general anesthesia in the 1940’s
NEUROMUSCULAR BLOCKING AGENTS fall into 2 classes
1. Nondepolarizing (competitive)
2. Depolarizing
Nondepolarizing (competitive)Blockers
tubocurarine--ISOQUINOLINE
mivacurium (Mivacron)
atracurium (Tracrium)
pancuronium (generic, Pavulon)--STEROID
rocuronium (Zemuron)
pipecuronium (Arduan)
Mechanism of action of Nondepolarizing (competitive)Blockers
Blocks N-R competitively-- INHIBITS Na- CHANNEL & EPP
REVERSIBLE; SURMOUNTABLE
Nondepolarizing (competitive)Blockers: Effects on skeletal muscle
Muscle paralysis
Sequence of paralysis:
Small, rapidly moving muscles are affected earliest – fingers, toes, jaws, eyes, etc.

Next, the muscles of the limbs, neck, trunk.

Last to be affected are the intercostal muscles and, finally, the diaphragm – death.

Recovery of muscles usually occurs in reverse order:
Diaphragm>limbs,trunks> fingers, toes, eyes
______________ can antagonize the effects of tubocurarine and other nondepolarizing NM blocking agents:

i.e., the block is “surmountable”-- increase ACH
Anticholinesterase drugs, e.g., neostigmine,edrophonium
Cardiovascular effects of Nondepolarizing (competitive)Blockers
With the exception of pipecuronium, & rocuronium, all nondepolarizing muscle relaxants produce some CV effects.
Tubocurarine can result in what CV event
PRONOUNCED HYPOTENSION due largely to histamine release and sympathetic ganglionic blockade.-- REFLEX TACHYCARDIA
Pancuronium can cause what CV complications
increase heart rate & BP --vagolytic.
mivacurium causes a moderate amount of ________ release
histamine
tubocurarine causes a moderate amount of ________ release and is a _________ of autonomic ganglia
histamine
weak block
Pancuronium is a ___________ of the cardiac muscarinic receptors
moderate blocker
Succinylcholine is a _________ of autonomic ganglia and a ___________ of the cardiac muscarinic receptors
stimulator
stimulator
Pharmacokinetics of nondepolarizing (competitive) neuromuscular blocking agents
Quaternary ammonium compounds-poorly absorbed from GI tract; I.V. (preferred) or I.M.

Following I.V. administration, get rapid redistribution phase followed by slower elimination phase.

Undergo varying degrees of liver metabolism; others are excreted in the urine.
Mivacurium duration of action

and degradation
Short-acting

plasma choninesterases
Vecuronium, atracurium duration of action
Intermediate-acting
Atracurium:
degredation & duration of action
degraded spontaneously

intermediate
Tubocurarine: duration of action
long acting
pancuronium: duration of action
long acting
pipercuronium: duration of action
long acting
rocuronium: duration of action
intermediate acting
vecuronium: duration of action
intermediate acting
Succinylcholine: duration of action

degredation
very short acting

plasma cholinesterases
Clinical uses of Nondepolarizing (Competitive) Blockers
Adjuncts to general anesthetics during surgery.

Controlled mechanical ventilation--COPD

Prevent trauma during convulsions
Nondepolarizing (Competitive) Blockers used during short surgical procedures
atracurium, mivacurium
Nondepolarizing (Competitive) Blockers used during Endotracheal intubation
rocuronium
Adverse reactions: Nondepolarizing (Competitive) Blockers

antagonized by
Prolonged apnea

cholinesterase inhibitors (e.g. neostigmine(Prostigmin))
Cautions, drug interactions:
Nondepolarizing (Competitive) Blockers
Respiratory depression
Myasthenia gravis
Renal impairment
Liver or CV impairment
drugs can enhance the effects of NM blocking agents
Inhalation anesthetics e.g. halothane

Antibiotics, esp. aminoglycosides - ?
↓ ACH RELEASE

Calcium channel blockers-?
↓ CA INFLUX

Antiarrhythmic agents (e.g., quinidine)-
BLOCKS Na-CHANNELS

Local anesthetics-?
Depolarizing Neuromuscular blocking drugs: MOA
Depolarization block-- FLACCID PARALYSIS Can be divided into two phases.

1) Phase I block: Depolarization, fasciculations, unresponsiveness with continued depolarization.

Potentiated by cholinesterase inhibitors -- increase ACh

2)Phase II block-“desensitization”: With continued exposure to succinylcholine, repolarization occurs but the membrane is NOT easily depolarized again.

Closely resembles a nondepolarizing block.(= CURARE)REVERSED BY AChE INHIBITORS
Depolarizing Neuromuscular blocking drugs: Effects on skeletal muscle
1) Brief muscular fasciculations precede paralysis.

2) Duration is brief ( i.e.5-10 MIN); can prolong effect by repeated injections.
Depolarizing Neuromuscular blocking drugs:Other effects:
1)Cardiac arrhythmias can occur;
- bradycardia prevented by atropine.

2)Hyperkalemia – can be life-threatening
• Cause:K-LOSS FROM mm
• Cautions in patients with burns, nerve damage, NM disease, children or digoxin

3)Slight histamine release
Pharmacokinetics:
Depolarizing Neuromuscular blocking drugs:
I.V.; short duration due to rapid inactivation by plasma cholinesterase

An unusually prolonged duration (apnea) will occur in patients with an abnormal variant of pseudocholinesterase. An Autosomal Recessive trait in ~ 1% of Caucasians but is rare in Asians and Blacks.-- IDIOSYNCRATIC

The “dibucaine number” – a test for ability to metabolize succinylcholine – can be used to screen such patients.
-- ENZYME RESISTANT TO DIBUCAINE INHIBITION (50% vs 80%)
Clinical uses of Depolarizing Neuromuscular blocking drugs
Adjunct to general anesthesia for brief procedures and to facilitate endotracheal intubation.

• Electroconvulsive therapy-- PREVENT CONVULSIONS
Adverse reactions of Depolarizing Neuromuscular blocking drugs
a. Apnea; hyperkalema, ↑intraocular P.
b. emesis, muscle pain; (up to 20%).
c. Malignant hyperthermia – life- threatening

• Results from a genetic defect of SR: SUDDEN & PROLONG RELEASE OF CA++ WITH MASSIVE MUSCLE CONTRACTION AND increased BODY TEMPERATURE
• The highest incidence occurs with succinylcholine + halothane.
• TX: COOLING, OXYGEN
DANTROLENE-- IV, DOC
Contraindications, cautions of Neuromuscular blocking drugs
•Genetic disorders of plasma cholinesterase

•History of malignant hyperthermia

• Acute angle-closure glaucoma-- ?

•Respiratory, liver, cardiovascular, renal disorders

•Electrolyte imbalance
Drug interactions with Neuromuscular blocking drugs
• Cholinesterase inhibitors

• Numerous drugs may enhance the NM blocking action:

- General anesthetics
- Antibiotics
- Quinidine
Spasticity
is ↑ skeletal muscle tone of CENTRAL ORIGIN – Increase in tonic stretch reflexes and flexor muscle spasms (together with muscle weakness).
The hyperactivity results from a loss of spinal and supraspinal descending inhibitory influences on motoneurons:
“upper motor neuron lesions.”
Clinical uses of Nondepolarizing (Competitive) Blockers
Adjuncts to general anesthetics during surgery.

Controlled mechanical ventilation--COPD

Prevent trauma during convulsions
Nondepolarizing (Competitive) Blockers used during short surgical procedures
atracurium, mivacurium
Nondepolarizing (Competitive) Blockers used during Endotracheal intubation
rocuronium
Adverse reactions: Nondepolarizing (Competitive) Blockers

antagonized by
Prolonged apnea

cholinesterase inhibitors (e.g. neostigmine(Prostigmin))
Cautions, drug interactions:
Nondepolarizing (Competitive) Blockers
Respiratory depression
Myasthenia gravis
Renal impairment
Liver or CV impairment
drugs can enhance the effects of NM blocking agents
Inhalation anesthetics e.g. halothane

Antibiotics, esp. aminoglycosides - ?
↓ ACH RELEASE

Calcium channel blockers-?
↓ CA INFLUX

Antiarrhythmic agents (e.g., quinidine)-
BLOCKS Na-CHANNELS

Local anesthetics-?
Depolarizing Neuromuscular blocking drugs: MOA
Depolarization block-- FLACCID PARALYSIS Can be divided into two phases.

1) Phase I block: Depolarization, fasciculations, unresponsiveness with continued depolarization.

Potentiated by cholinesterase inhibitors -- increase ACh

2)Phase II block-“desensitization”: With continued exposure to succinylcholine, repolarization occurs but the membrane is NOT easily depolarized again.

Closely resembles a nondepolarizing block.(= CURARE)REVERSED BY AChE INHIBITORS
Depolarizing Neuromuscular blocking drugs: Effects on skeletal muscle
1) Brief muscular fasciculations precede paralysis.

2) Duration is brief ( i.e.5-10 MIN); can prolong effect by repeated injections.
Depolarizing Neuromuscular blocking drugs:Other effects:
1)Cardiac arrhythmias can occur;
- bradycardia prevented by atropine.

2)Hyperkalemia – can be life-threatening
• Cause:K-LOSS FROM mm
• Cautions in patients with burns, nerve damage, NM disease, children or digoxin

3)Slight histamine release
Pharmacokinetics:
Depolarizing Neuromuscular blocking drugs:
I.V.; short duration due to rapid inactivation by plasma cholinesterase

An unusually prolonged duration (apnea) will occur in patients with an abnormal variant of pseudocholinesterase. An Autosomal Recessive trait in ~ 1% of Caucasians but is rare in Asians and Blacks.-- IDIOSYNCRATIC

The “dibucaine number” – a test for ability to metabolize succinylcholine – can be used to screen such patients.
-- ENZYME RESISTANT TO DIBUCAINE INHIBITION (50% vs 80%)
Clinical uses of Depolarizing Neuromuscular blocking drugs
Adjunct to general anesthesia for brief procedures and to facilitate endotracheal intubation.

• Electroconvulsive therapy-- PREVENT CONVULSIONS
Adverse reactions of Depolarizing Neuromuscular blocking drugs
a. Apnea; hyperkalema, ↑intraocular P.
• Apnea best treated by mechanical ventilation. Cholinesterase inhibitors will antagonize only Phase II.
b. emesis, muscle pain; (up to 20%).
c. Malignant hyperthermia – life- threatening

• Results from a genetic defect of SR: SUDDEN & PROLONG RELEASE OF CA++ WITH MASSIVE MUSCLE CONTRACTION AND increased BODY TEMPERATURE
• The highest incidence occurs with succinylcholine + halothane.
• TX: COOLING, OXYGEN
DANTROLENE-- IV, DOC
Contraindications, cautions of Neuromuscular blocking drugs
•Genetic disorders of plasma cholinesterase

•History of malignant hyperthermia

• Acute angle-closure glaucoma-- ?

•Respiratory, liver, cardiovascular, renal disorders

•Electrolyte imbalance
Drug interactions with Neuromuscular blocking drugs
• Cholinesterase inhibitors

• Numerous drugs may enhance the NM blocking action:

- General anesthetics
- Antibiotics
- Quinidine
Spasticity
is ↑ skeletal muscle tone of CENTRAL ORIGIN – Increase in tonic stretch reflexes and flexor muscle spasms (together with muscle weakness).
The hyperactivity results from a loss of spinal and supraspinal descending inhibitory influences on motoneurons:
“upper motor neuron lesions.”
what is spasticity associated with
The hyperactivity results from a loss of spinal and supraspinal descending inhibitory influences on motoneurons: “upper motor neuron lesions.”

Spasticity is associated with strokes, CNS injuries, cerebral palsy, and multiple sclerosis

Drugs may ameliorate some of the symptoms of spasticity by modifying the stretch reflex arc or by interfering directly with the process of excitation contraction coupling in the muscle.
Spamolytic Drugs:
A. Benzodiazepines: Diazepam(Valium)
B. Baclofen (generic, Lioresal)
C. Tazanidine (Zanaflex)
Drugs Act Directly at Skeletal Muscle
A Dantrolene (Dantrium)
B. Botulinium Toxin Type A (Botox)
Benzodiazepines: Diazepam (Valium) -- MOA
ENHANCED GABA-MEDIATED
PRESYN. INHIBITION
Benzodiazepines: Diazepam (Valium)

Uses:
Spastic states and spasm due to local muscle trauma; SEDATION -- at the doses required (2 – 10 mg 4X per day)-- LIMITING Greatest benefit seen in patients with multiple sclerosis and spinal cord injury.
Benzodiazepines: Diazepam
Cautions
Psychological and physical dependence can occur (Schedule IV):
Baclofen (Lioresal)
MOA:
GABA AGONIST--HYPERPOLARIZATION---PRESYN. INHIBITION
Results in inhibition of release of excitatory transmitters (e.g., glutamic acid; aspartic acid) involved in spinal reflex pathways.
Baclofen (Lioresal)
Effects:
Very effective in relieving involuntary flexor spasms and resistance to passive movements; LESS sedating than diazepam.
Baclofen (Lioresal)Pharmacokinetics:
a. Well absorbed orally; intrathecal via an implantable infusion pump.

b. Widely distributed, excreted primarily by the kidney unchanged. Plasma half-life is 3-4 hours.
Baclofen (Lioresal)
Adverse reactions:
a. Drowsiness, lassitude, dizziness.

b. Ataxia, confusion, hallucinations, seizures.

c. Intrathecal: coma, respiratory depession, seizures.
Baclofen (Lioresal)
Cautions, drug interactions.
•Hallucinations, psychosis, and seizures have been reported upon withdrawal; AVOID abrupt withdrawal.
•Impaired renal function
•Epilepsy
•CNS depressants
Baclofen (Lioresal)
uses:
•Spasticity in patients with multiple sclerosis and spinal cord injury; trigeminal neuralgia

•Begin with low oral dose and gradually ↑ to 40 – 80 mg/day in divided doses.
Tizanidine (Zanaflex)
MOA
Structurally related to clonidine.

Alpha-2 agonist--
↑ PRESYN. INHIBITION OF MOTOR NEURONS.
Also inhibits nociceptive transmission in the spinal cord.
Tizanidine (Zanaflex)
Side effects:
• Asthenia (41%); WEAKNESS
• Drowsiness, hypotension and dry mouth.
DRUGS ACT DIRECTY ON SKELETAL MUSCLE
Dantrolene (Dantrium)
Dantrolene (Dantrium)
MOA:
May bind to the ryanodine receptors on the calcium channel of the SR. DECREASE Ca++ RELEASE AND E-C COUPLING IN SK. M.
Dantrolene (Dantrium)
Effects:
Usually diminishes spasticity but, tends to cause generalized muscle weakness
Dantrolene (Dantrium)Pharmacokinetics:
Oral absorption is slow and incomplete; I.V. for malignant hyperthermia.

b.Slowly metabolized in the liver(hydroxylated). Half-life is about 8 hrs.
Dantrolene (Dantrium)
Adverse reactions:
a.Muscle Weakness, drowsiness

b.Severe liver toxicity, potentially fatal hepatitis.
Dantrolene (Dantrium)
Contraindications, cautions:
•Liver disease

•Ambulatory patients—caution

•Perform liver function tests periodically

•Patients over age of 35, esp females
Dantrolene (Dantrium)
Clinical uses:
•Spasticity of cerebral origin—oral.

•Malignant hyperthermia—I.V. DOC
Botulinum toxin type A (Botox)
Where is it obtained
clostridium botulinum
Botulinum toxin type A (Botox)
How is it given
IM.
Botulinum toxin type A (Botox)
MOA:
•↓ ACH RELEASE & NM CONDUCTION-- M. PARALYSIS; REDUCE WRINKLES
• Muscle function returns gradually over 3 – 6 months.
Botulinum toxin type A (Botox)
Uses:
•Strabismus, blepharospasm
•Cervical dystonia (spasmodic toricollis); writer’s cramp; spasms due to M.S. or cerebral palsy.
•Reduces wrinkles or frown lines
Botulinum toxin type A (Botox)
Adverse reactions:
• Dysphagia (20%), dyspnea, aspiration, pneumonia

• Muscle weakness, dyspepsia and pain at injection site.

• Severe headache; temporary ptosis, drooling and asymmetrical smile.
DRUGS USED FOR ACUTE LOCAL MUSCLE SPASM:

“CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS”
cyclobenzaprine(generic,Flexeril)

carisoprodol (generic, Soma)
uses and considerations of DRUGS USED FOR ACUTE LOCAL MUSCLE SPASM:
Most muscle strains and minor injuries are self-limited and respond rapidly to rest and physical therapy—immobilization, cold compresses, whirlpool baths, etc.


These drugs may provide some symptomatic relief in localized muscle spasm; all are CNS depressants and act as sedatives.
Cyclobenzaprine (Flexeril):
is sxlly related to _______

has some ___________ at doses of 30 mg

Has strong __________effects
tricyclic antidepressants.

adjunctive muscle relaxant capabilities

antimuscarinic
Cyclobenzaprine (Flexeril):
Adverse reactions:
Sedation, dry mouth, dizziness.

Tachycardia, blurred vision, confusion,visual hallucination, urinary retention
Cyclobenzaprine (Flexeril):
Cautions:
urinary retention
glaucoma
CASE STUDY
A patient underwent a surgical procedure lasting 2 hours. Anesthesia was provided by isoflurane, supplemented by intravenous midazolam and a nondepolarizing muscle relaxant.At the end of the procedure, glycopyrrolate, an antimuscurinic agent,was administered followed by pyridostigmine.
SEE NEXT
--
The main reason for administering glycopyrrolate is to:

a.Dry secretions induced by isoflurane

b.Reverse the effects of the muscle relaxant

c.Provide postoperative analgesia

d.Prevent activation of cardiac muscarinic receptors

e.Enhance the action of pyridostigmine
--
Glycopyrrolae would be LEAST likely to be needed during reversal of the effects of a nondepolarizing relaxant if the agent used was:

a. Atracurium

b. Mivacurium

c. Pancuronium

d. Tubocurarine

e. Vecuronium
--
Case 2:
A 22-year-old patient was given a bolus intravenous dose of a drug for muscle relaxation that should have lasted only 5-10 minutes. Instead, the patient required mechanical ventilation for over 8 hours. Which one of the following statements about this problem is LEAST accurate?

a. The agent administered was succinylcholine

b. Fewer than 1:2500 persons have the homozygous trait responsible for this type of problem.

c. Pseudocholinesterase in this patient is resistant to the inhibitory action of dibucaine.

d. About 1:500 persons may experience a slight prolongation of NM blockade when given this agent, i.e., have the heterozygous trait.

e. Neostigmine should be administered to establish the nature of the problem.
--
How is apnea best treated
• Apnea best treated by mechanical ventilation. Cholinesterase inhibitors will antagonize only Phase II