Neuromuscular Junction/Ganglia Drugs

Question 1

Rocuronium

Answer 1

Intermediate-acting agent
Rapid onset and lower potency; an alternative to succinylcholine.
Uses: rapid induction anesthesia, relax laryngeal and jaw muscles to facilitate tracheal intubation.
No tachycardia
Hepatic elimination
Competitive blocker

Question 2

D-tobucurarine

Answer 2

Natural alkaloid
Long duration, competitive.
No longer in USA-seldom used.
Renal and hepatic elimination.
Newer agents are used because of shorter duration of action, diminished frequency of side effects (ganglionic blockade, block of vagal responses, and histamine release).
Inability ot penetrate BBB.
Blockage at autonomic ganglia and muscarinic sites:
Fall in BP and tachycardia.
Reversed by anti-ChE agents
Partial blockade at autonomic ganglia and adrenal medulla.
Atracurium, vecuronium, doxacurium, mivacurium, rocuronium are more selective.
Prevents depolarization by ACh
Causes flaccid paralysis
Weak block of cardiac muscarinic ACh receptors.
Can cause histamine release with hypotension.

Question 3

Pancuronium

Answer 3

No histamine release.
Long duration, competitive.
Blocks muscarinic receptors (vagal blockade and tachycardia).
Less ganglionic blockade at common clinical doses.
Renal and hepatic elimination

Question 4

Vecuronium

Answer 4

Ammonio steroid.
No tachycardia
Intermediate duration, competitive.
Hepatic and renal elimination.
Metabolized in the liver.
Competitive antagonist at nACh receptors especially at NMJ.
No histamine release and minimal antimuscarinic effect.

Question 5

Atracurium

Answer 5

Benzylisoquinolones
Intermediate duration, competitive.
No vagolytic and ganglionic blocking actions.
Some histamine release.
Degraded by 2 routes:
1. Hydrolysis of the ester by plasma esterases.
2. Spontaneous (Hofmann) degradation: N alkyl cleavage.
Routes remain functional renal failure.

Question 6

Mivacurium

Answer 6

Benzylisoquinolones
Short duration, competitive
VERY sensitive to catalysis by cholinesterase or other plasma hydrolyses (explains short duration of action).
Slight histamine release.

Question 7

Cisatracurium

Answer 7

Benzylisoquionolones
10 cis isomers
Intermedia duration, competitive.
Hofmann and renal elimination.
Fewer adverse side effects then atracurium.

Question 8

Competitive vs depolarizing agents

Answer 8

Competitive: Bulky, rigid molecules
-Block the binding of ACh, which diminishes the amplitude of the EPP and becomes insufficient to initiate muscle AP.
-Reduces the frequency of channel opening events, but does not effect conductance or duration of opening for a single channel.
One molecule of antagonist is sufficient block one receptor, but need simultaneous binding of two agonist modules for receptor activation.
Constant distance between quaternary groups.
Depolarizing: more flexible structures that enable bond rotation (succinylcholine).
-Initially, depolarize membrane by opening channels like ACh does.
-They persist longer at the NMJ because resistance to acetylcholinesterase.
-Brief period of repetitive excitation
-Transient muscle fasciculation
-Then, get NMJ block and flaccid paralysis, because ACh is binding to receptors that are already depolarized; -80 to -55 depolarization is resistance to more depolarization by ACh.
Sequence of repetitive excitation (fasciculations) followed by block influencing factors.
Anesthetic agent used concurrently.
With increasing concentrations…the black may convert from a depolarizing to a non depolarizing type (phase 1 to a phase 2 block).

Question 9

Botulinum Toxin

Answer 9

Interferes with the synthesis and release of ACh.
Administer locally to muscles of the orbit.
Controls muscle spasms and facial muscle relaxation.
Can treat achalasia by injection into lower esophageal sphincter.

Question 10

Dantrolene

Answer 10

Blocks Ca2+ release from SR.

Used in the treatment of MALIGNANT HYPERTHERMIA!!!

Question 11

Sequence and characteristics of paralysis: competitive blocking agent

Answer 11

Intravenous injection
Motor weakness progresses to total flaccid paralysis.
First, the small rapid moving muscles like the eyes, jaw, and larynx relax.
Later, muscles of the limbs and trunk relax.
Recovery of muscles usually occurs in the reverse order of their paralysis.
Diaphragm is the first muscle to regain function.

Question 12

Sequence and characteristics of paralysis: depolarizing agent (succinylcholine)

Answer 12

Intravenous injection
Muscle fasiculations over chest and abdomen occur briefly.
Relaxation occurs within 1 minute.
Becomes maximal within 2 minutes; transient apnea occurs.
Disappears as a rule within 5 minutes.
After infusion, effects of drug disappear rapidly.
Muscle soreness may follow.
Muscle relaxation of longer duration is achieved by continuous IV injection.

Question 13

Succinylcholine

Answer 13

Rarely causes effects attributable to ganglionic blockade at doses producing neuromuscular relaxation.
CV effects observed due to successive stimulation: vagal ganglia manifested by bradycardia; sympathetic ganglia causing hypertension and tachycardia.

Question 14

Histamine Release

Answer 14

-Direct action of muscle relaxant on mast cell; not IgE-mediated anaphylaxis.
Tubocurarine-injected intracutaneously or intra-arterially produces typical histamine-like raised reddened marks (wheals).
Clinical responses to neuromusscular blocking agents: bronchospasm, hypotension, excessive bronchial and salivary secretion: caused by the release of HISTAMINE.
Succinylcholine, mivacurium, atrcurium, doxacurium cause histamine release to a lesser extent unless administered rapidly.
Ammonio steroids, pancuronium, vecuronium, and rocuronium have less tendency to release histamine after intradermal or systemic injection.

Question 15

Succinylcholine: Life Threatening Implications

Answer 15

Release K+ rapidly from intracellular sites
-May be a factor in production of apnea in patients in electrolyte imbalance.
Induced hyperkalemia:
Life threatening
Depolarizing blocking agents should be avoided in patients with predisposition to redistribution of K+ (congestive heart failure patients and burn victims).
Higher doses of a competitive blocking agent should be used instead.
Succinylcholine cautions:
-Patients with…
rhabdomyolysis
ocular lacerations
spinal cord injuries with paraplegia or quadriplegia
muscular dystrophies
Not for children 8 years old and younger EXCEPT when emergency intubation and securing an airway is necessary.

Question 16

Toxicology of Neuromuscular Blocking agents

Answer 16

• Prolonged apnea
• CV collapse
• Responses resulting from histamine release
• Anaphylaxis rarely occurs
• Failure of adequate respiration in postop period: not always die directly to excessive muscle paralysis from drug.
• could be from airway obstruction or decreased PCO2 from hyperventialtion.
• directly related factors: body temperature, electrolyte imbalance, altered physiology and disease states.

Question 17

Malignant Hyperthermia

Answer 17

Life threatening event
Triggered by administration of some anesthetics and neuromuscular blockers.
Due to uncontrolled release of Ca2+ from SR of skeletal muscle.
Clinical features: contracture, rigidity and heat production from skeletal muscle.
Hyperthermia (overheated), accelerated muscle metabolism, metabolic acidosis and tachycardia.
Susceptibility to malignant hyperthermia:
No clinical signs visible in the absence of anesthetic intervention.
Linkage between the contracture test on fresh biopsy of skeletal muscle and a mutation in the ryanodine receptor (on sarcoplasmic reticulum); others on L type Ca2+ channels.
Treatment: IV injection of DANTROLENE (limits the capacity of Ca2+ and calmodulin to activate Ryr-1).
Rapid cooling, inhalation of 100% oxygen and control of acidosis.

Question 18

Phase 1 Neuromuscular blockade by succinylcholine

Answer 18

EPP: depolarized to -55
Immediate onset
Lower dose-dependence
Rapid recovery
Augments antichilinesterae inhibition.
Muscle response: Fasciculations-> flaccid paralysis.
Train of four and tetanic stimulation: no fade

Question 19

Phase 2 Neuromuscular blockade by succinylcholine

Answer 19

EPP: Repolarization toward -80
Slow transition onset
Higher dose dependence or follows prolonged infusion
Prolonged recovery
Train of four and titanic stimulation: fade
Anticholinesterse inhibition: reverses or antagonizes
Muscle response: flaccid paralysis

Question 20

Respiratory paralysis

Answer 20

Cause: adverse reaction or overdose of neuromuscular blocking agent
Treatment: positive-pressure artificial respiration with oxygen, maintenance of patient airway.
Hastening of treatment: Administration of neostigmine methyl sulfate or edrophonium IV (short half life so repeat is required).

Question 21

Other toxic effects…

Answer 21

Use NEOSTIGMINE

• Antagonizes only the skeletal muscular blocking action of the competitive blocking agents,
• May aggravate side effects of hypotension or induce bronchospasm; sympathomimetic amines may be given to support BP.
• Atropine or glycopyrolate is administered to counteract muscarinic stimulation.
• Antihistamines definitely beneficial: counteract the responses that follow release of histamine, useful when administered before the neuromuscular blocking agent.

Question 22

Therapeutic uses of Neuromuscular blocking agents

Answer 22

MAIN CLINICAL USE IS AS AN ADJUVANT IN SURGICAL ANESTHESIA TO OBTAIN RELAXATION OF SKELETAL MUSCLE, PARTICULARLY OF ABDOMINAL WALL, TO FACILITATE OPERATIVE MANIPULATIONS.
Reasons for use:
Much lighter levels of anesthesia can be used.
The risk of respiratory and CV depression if minimized,
Post anesthetic recovery is shortened,
Uses:
NMJ blocking agents be used to substitute for inadequate anesthesia depth; the risk of reflex responses to painful stimuli and conscious recall may occur.
Orthopedic procedures.
Facilitate intubation with an endotracheal tube and bronchoscopy and other procedures like this.
Used in combination with other anesthetic agents.
Administration:
Parenterally: nearly always IV,
Potentially hazardous drugs

Question 23

Use to prevent trauma during electroshock therapy

Answer 23

The seizures induced by this treatment may cause dislocations or fractures.
Succinylcholine or mivacurium used because of the brevity of relaxation.

Question 24

Use in the control of muscle spasms

Answer 24

Used to treat spasticity involving the alpha motor neuron with the objective of increasing the functional capacity and reliving discomfort.
Agents that act in the CNS: act at either higher centers or the spinal cord to block spasms.
BACLOFEN, BENZODIAZEPINES, TIZANDINE
Agents that act peripherally:
-Botulinum toxin A: produces flaccid paralysis of skeletal muscle, diminished activity of parasympathetic synapses, diminished activity of sympathetic cholinergic synapses, restoration of function requires nerve sprouting.
-Dantrolene: causes a generalized weakness; treatment of spasticity and hyperreflexia, should be reserved for non ambulatory patients with severe spasticity; hepatotoxicity reported with continued use.

Question 25

Ganglionic neurotransmission

Answer 25

These events are INSENSITIVE TO NICOTINIC ANTAGONISTS and include the slow EPSP, late slow EPSP, and IPSP.

1. Slow EPSP: Blocked by atropine or antagonists that are selective for M1 muscarinic receptors.
2. Late slow EPSP: unaffected by the classical nicotinic receptor blocking agents.
3. IPSP: Unaffected by the classical nicotinic receptor blocking agents; IPSP and catecholamine-induced hyper polarization are blocked by adrenergic antagonists.

Question 26

Drugs that stimulate cholinergic receptor sites on autonomic ganglia

Answer 26

1. Drugs with nicotinic specificity including nicotine itself
   Excitatory effects on ganglia are rapid in onset
   Effects are blocked by ganglionic nicotinic receptor antagonists.
   Mimic the initial EPSP.
2. Agents such as muscarine, McN-A-343 and methacholine.
   Excitatory effects on ganglia are delayed in onset.
   Effects are blocked by atropine-like drugs.
   Mimic the slow EPSP.

Question 27

Ganglionic blocking agents acting on the nicotinic receptor

Answer 27

1. Drugs that initially stimulate the ganglia by an AcH-like action and then block them
   The block is because of persistent depolarization (Ex: nicotine).
2. Blockade of autonomic ganglia (hexamethonium)
   Agents impair transmission in one of two ways:
3. competing with AcH for ganglionic nicotinic receptor sites
4. blocking the channel
   The net effect is that the initial EPSP is blocked and the ganglionic transmission is inhibited.

Question 28

Nicotine

Answer 28

Ganglionic stimulating drug
This drug is of medical significance because of its toxicity, presence in tobacco, and propensity for conferring a dependence on its users.
One of the few natural liquid alkaloids.
Actions:
Complex and often unpredictable changes after administration.
This is due to its actions on a variety of neuroeffector and chemosensitive sites.
Also due to the fact that the alkaloid can stimulate and desensitize receptors.
Summation of stimulatory and inhibitory effects.
Example: Excitation of sympathetic cardiac ganglia and paralysis of parasympathetic cardiac ganglia.
Effects chemoreceptors of the carotid and aortic bodies.
brain centers, CV compensatory reflexes resulting from changing heart rate (all can influence heart rate).
Nicotine elicits a discharge of epinephrine from the adrenal medulla; this accelerates the heart rate and raises BP.

Question 29

Nicotine and the peripheral nervous system

Answer 29

THE MAJOR ACTION OF NICOTINE CONSISTS INITIALLY OF TRANSIENT STIMULATION AND SUBSEQUENTLY OF A MORE PERSISTENT DEPRESSION OF ALL AUTNOMIC GANGLA. SMALL DOSES OF NICOTINE STIMULATE THE GANGLION CELLS DIRECTLY AND MAY FACILITATE IMPULSE TRANSMISSION. WHEN LARGER DOSES OF THE DRUG ARE APPLIED, THE INITIAL STIMULATION IS FOLLOWED VERY QUICKLY BY A BLOCKADE OF TRANSMISSION.
Adrenal Medulla: biphasic action
Small doses evoke the discharge of catecholamines
Larger doses prevent catecholamine release due to splanchnic nerve stimulation.
NMJ: Stimulant phase is obscured largely by the rapidly developing paralysis; nicotine produces neuromuscular blockade by receptor desensitization.

Question 30

Nicotine and the CNS

Answer 30

Markedly stimulates.
Dose dependent; low dose produces weak analgesia (inability to feel pain).
Higher doses produce tremors, leading to convulsions at toxic doses.
Excitation of respiration; large doses act directly on the medulla oblongata, smaller doses augment (increase) respiration.
Stimulation of CNS with large doses is followed by depression and death results from failure of respiration.
Vomiting
Higher brain centers: stimulatory and pressure-reawrd actions of nicotine.
Chronic exposure causes a marked increase in the density or number of nicotinic receptors.

Question 31

Doxacurium

Answer 31

No longer in USA
Benzylisoquinone
Long duration, competitive
Renal elimination.

Question 32

Nicotine and the CV system

Answer 32

IV nicotine: produces an increase in heart rate and BP; BP increase is usually more sustained.
Stimulation of sympathetic ganglia and adrenal medulla.
Discharge of catecholamines from sympathetic nerve endings.
Activation of chemoreceptors of the aortic and carotid bodies: reflexly results in vasoconstriction, tachycardia, and elevated BP.
Combined activation of parasympathetic ganglia any cholinergic nerve endings: increased tone and motor activity of the bowel.

Question 33

Nicotine and Exocrine Glands

Answer 33

Initial stimulation of salivary and bronchial secretions.

This is followed by inhibition.

Question 34

Absorption, fate and excretion of Nicotine

Answer 34

Sites where nicotine is readily absorbed: respiratory tract, buccal membranes, and skin.
Severe poisoning has resulted from percutaneous absorption.
It is a relatively strong base, so its absorption from the stomach is limited; intestinal absorption is much more efficient.
Metabolism: 80-90% is altered in the body. MAINLY IN THE LIVER, but also in the kidney and lung.
Cotinine is the major metabolite.
Half life of nicotine following inhalation or parenteral administration is about 2 hours.
Elimination: Nicotine and metabolites are eliminated rapidly by the kidney.
The rate of urinary excretion of nicotine diminishes when urine is alkaline.
Nicotine also excreted in milk of lactating women who smoke.

Question 35

Ganglionic Blocking Drugs

Answer 35

Blockade of sympathetic ganglia; interrupts adrenergic control of arterioles: vasodilation, improved peripheral blood flow in some vascular beds and a fall in BP.
Reduced cardiac output because of diminished venous return (venous dilation and peripheral pooling of blood)-normal cardiac patients.
Increased cardiac output in patients with cardiac failure (reduction in peripheral resistance).
Hypertensive patients: diminished cardiac output, stroke volume, and left ventricular work.
Total systemic vascular resistance is decreased in patients who receive blocking agents.
Reduction of cerebral blood flow is small.
Skeletal muscle blood flow is unaltered.
Splanchnic and renal blood flow decrease.
General undesirable ganglionic blockade results that limit therapeutic efficacy:
-Atony of bladder and GI tract.
-Cycloplegia, xerostomia, diminished perspiration.
-Postural hypotension by abolishing circulatory reflex pathways.
Untoward responses and severe reactions:
1. Milder: visual disturbances, dry mouth, urinary hesitancy, conjunctival suffusion; decreased potency, subjective chilliness, moderate constipation, occasional diarrhea; abdominal discomfort, anorexia, heartburn, nausea, eructation; bitter taste, and the signs and symptoms of syncope caused by postural hypotension.
2. More severe: marked hypotension, constipation, syncope, paralytic ileus, urinary retention, cycloplegia.

Question 36

Absorption, fate and excretion-ganglionic blocking drugs

Answer 36

Absorption of quaternary ammonium and sulfonium compounds from the enteric tract; incomplete and unpredictable because:
1. limited ability of these ionized substances to penetrate cell membranes.
2. Depression of propulsive movements of the small intestine and gastric emptying.
Extracellular space.
Excreted mostly unchanged by kidney.
Absorption of MECAMYLAMINE:
Less erratic
Danger exists of reduced activity leading to frank paralytic ileus.
Concentrates in the liver and kidney-excreted slowly in unchanged form.

Question 37

Therapeutic uses of Mecamylamine

Answer 37

Only ganglionic blocker currently available in USA.
Selectively antagonizes Nn receptors.
Also blunts sympathetic reflexes.
There are superior agents for treatment of chronic hypertension.
Alternative agents available for management of acute hypertensive crises.
Production of controlled hypotension:
-Reduction of BP during surgery to minimize hemorrhage
-Reduce blood loss in orthopedic procedures
-Facilitate surgery on blood vessels.
-Supplanted (replaced) largely by nitroprusside or depressor sedatives.

Question 38

Baclofen

Answer 38

Centrally acting spasmolytic drug
GABAb agonist 
Facilitates spinal inhibition of motor neurons.
Pre and post synaptic inhibition of motor output.
Treats MS, cerebral palsy spasticity.
Stroke
Oral, intrathecal routes
Adverse effects: sedation, weakness.