General Pharmacology

1. General Pharmacology Neuromuscular Blocking Agents S. HabibianDehkordiD.V.M Ph.D

2. 0 Neuromuscular blocking drugs • Extract of vines (Strychnos toxifera; also Chondrodendron species) • Used by indegenous peoples of Amazon basin in poison arrows (not orally active, so food is safe to eat) • Brought to Europe by Sir Walter Raleigh, others • Curare-type drugs: Tubocurare (bamboo tubes), Gourd curare, Pot curare • Brody (1811) showed curare is not lethal is animal is ventilated • Harley (1850) used curare for tetanus and strychnine poisoning • Harold King (1935) isolates d-tubocurarine from a museum sample – determines structure.

3. 0 Neuromuscular blocking drugs • Block synaptic transmission at the neuromuscular junction • Affect synaptic transmission only at skeletal muscle • Does not affect nerve transmission, action potential generation • Act at nicotinic acetylcholine receptor NII

4. 0 Neuromuscular blocking drugs (CH3)3N+-(CH2)6-N+(CH3)3 Hexamethonium (ganglionic) (CH3)3N+-(CH2)10-N+(CH3)3 Decamethonium (motor endplate)

5. 0 Neuromuscular blocking drugs • Acetylcholine is released from motor neurons in discrete quanta • Causes “all-or-none” rapid opening of Na+/K+ channels (duration 1 msec) • Development of miniature end-plate potentials (mEPP) • Summate to form EPP and muscle action potential – results in muscle contraction • ACh is rapidly hydrolyzed by acetylcholinesterase; no rebinding to receptor occurs unless AChE inhibitor is present

6. Neuromuscular Blocking Agents These Drugs prevent interaction between Ach and Nicotinic receptors in the skeletal muscles Final results: Temporary Paralysis of skeletal muscles and muscle relaxation Clinical uses In the general anesthesia, they are used to a) facilitate Tracheal intubation, b) induce muscle relaxation, c) make orthopedic surgery easy, d) reduce the dose of anesthetics Mechanism of action 1- Some occupy the receptors and prevent Ach action competitively 2- Some which are so-called depolarizing agents block receptors

7. Classification of Muscle RelaxantsAccording to Mechanism of Action Depolarizing , Non competitive, agonist. Succinylcholine Non depolarizing, Competitive, antagonist. Tubocurarine

8. Depolarizing Agents • Prototype of depolarizing agent is succinylcholine (only depolarizing drug in clinical use). • Mechanism of Action: Similar action to ACh, but longer acting. • Phase 1: Membrane is depolarized by opening AChR channels causing brief period of muscle fasciculation. • Phase II: End-plate eventually repolarizes, but because succinycholine is not metabolized like ACh it continues to occupy the AChRs to “desensitize” the end-plate. • Because of the mechanism of action of depolazing drugs is similar to ACh, their blocking effects are augmented by AChE inhibitors.

9. 0 Depolarizing Neuromuscular blocking drugs • Succinylcholine, decamethonium • Bind to motor end-plate and cause immediate and persistent depolarization • Initial contraction, fasciculations • Muscle is then in a depolarized, refractory state • Desensitization of Ach receptors • Insensitive to K+, electrical stimulation • Paralyzes skeletal more than respiratory muscles

10. Depolarizing Agents • Therapeutic Use: Adjuvant drugs in surgical anesthesia • Pharmacology: Duration of action is short (several minutes) because it is rapidly broken down by plasma cholinesterases (must be administered by continuous infusion) • Adverse Effects: When administered with halothane some genetically susceptible people (inherited autosomal dominant condition) experience malignant hyperthermia. Treatment: rapid cooling of the body and dantrolene

11. Non-depolarizing (competitive). • Prototype of Non-depolarizing is tubocurarine (new generation: pancuronium and gallamine). • Mechanism of Action: In small clinical doses they act the predominantly at the nicotinic receptor site to block ACh. • At higher does they can block prejunctional Na channels thereby decreasing ACh release. • Because of the competitive nature of the postsynaptic blockade, transient relief of the block can be achieved by increasing ACh levels at the synaptic cleft (i.e. use cholinesterase inhibitors).

12. 0 Non-depolarizing Neuromuscular blocking drugs • Competetive antagonist of the nicotinic 2 receptor • Blocks ACh from acting at motor end-plate • Reduction to 70% of initial EPP needed to prevent muscle action potential • Muscle is insensitive to added Ach, but reactive to K+ or electrical current • AChE inhibitors increase presence of ACh, shifting equilibrium to favor displacing the antagonist from motor end-plate

13. 0 Nondepolarizing drugs: Metabolism • Important in patients with impaired organ clearance or plasmacholinesterase deficiency • Hepatic metabolism and renal excretion (most common) • Atracurium, cis-atracurium:nonenzymatic (Hoffman elimination) • Mivacurium: plasma cholinesterase

14. Nondepolarizing Agents • Therapeutic Use: Adjuvant drugs in surgical anesthesia • Pharmacology: Must be given by injection because they are poorly absorbed orally. Do not cross the BBB. Generally excreted unchanged (i.e. not metabolized). • Adverse Effects: Tubocurarine causes release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals. Newer generation don’t.

15. Drug Interactions: • Cholinesterase Inhibitors decrease the effectiveness of nondepolarizing agents • Aminoglycoside antibiotics (e.g. streptomycin) decrease ACh release by competing with Ca2+ – increase action of nondepolarizing drugs • Calcium channel blockers increase the actions of nondepolarizing drugs by decreasing the amount of ACh released (i.e. increase action of nondepolarizing drugs) • Halogenated carbon anesthetics (e.g. Isoflurane) enhance neuromuscular blockade by 1) decreasing excitability of motoneurons, 2) increasing muscle blood flow, and 3) decreased kinetics of AChRs (increase action of nondepolarizing drugs)

16. Classification of Muscle RelaxantsAccording to Mechanism of Action Ultra-ShortShortIntermediateLong Succinylcholine Mivacurium VecuroniumPancuroniumAtracuriumRocuronium Cis-atracurium

17. Factors that affect their duration of action: 1-PH: changes metabolic acidosis and to a lesser extent respiratory acidosis extend the blockage duration 2-body temperature: Hypothermia potentiate the blockage duration. 3-age: Older patients have prolonged effect also. 4-electrolytes changes: Decrease in serum potassium conc. potentiate the blockageDecrease in ionized calcium conc. also potentiate the blockage Note: Concomitant administration of potent inhalational agents potentiate the duration of blockage esp. with isoflurane, enflurane and sevoflurane.

18. Classification based on chemical structures 1- drugs Molecoles are large, balk and nonflexible. They arecompetitive blocking drugs D-tubocurarine, Dimethyl (or Trimethyl) tubocurarine, Gallamine and Pancuronium 2- Drug’s molecules are small, rod shape and flexible. They are depolarizing agents Succinylcholine, Decamethonium سم مار کبری (Cobra neurotoxin) یا- bungarotoxinα Pharmacologic Consideration:

19. Skeletal Muscle: Comparative neuromuscular blocking agents: Depolarizing neuromuscular blocking agents: CNS: They have no effect on CNS Autonomic effects: Nicotinic receptors in the autonomic ganglia are less sensitive than in the somatic ganglia Effects of neuromuscular blocking agents on Muscaranic receptors are very small Histamine Release: Neuromuscular blocking agents cause histamine releasing

20. Factors Prolonging the neuromuscular blocakde • Neonates • Old age • Obesity • Hepatic disease (both depolarizer & NMDR) • Renal disease ( only NDMR) • Inhalational agents : Prolong the block by both depolarizers & NDMR. Inhalational agents decrease the requirement of relaxant .The maximum relaxation is by ether followed by desflurane • Antibiotics: Both depolarizers & NMDR • Aminoglycosides. • Tetracyclines.

21. Local Anaesthetics : Except procaine local anaesthetics prolong the action by stabilizing post synaptic membrane. • Hypothermia : Decreases metabolism of muscle relaxants. • Hypocalcemia: Calcium is required for producing action potential. Action of NDMR is enhanced. • Hypokalemia : NMDR block is enhanced. • Acid base imbalances especially acidosis. • Calcium channel blockers • Dantrolene • Neuromuscular disease • Hypermagnesemia.

22. Drugs which antagonise Neuromuscular Blockade • They reverse the block by NDMR only • Phenytoin • Carbamazepine • Calcium • Cholinesterase inhibitors • Azathioprine • Steroids.

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