Antinicotinics 1

Classification of Antinicotinics Antinicotinics Neuromuscular Junction blockers (NMJ) Ganglionic blockers 2

Neuro Muscular Junction blockers (NMJ) These are the drugs that prevent interaction of Ach at Nicotinic receptor at Neuro muscular Junction NMJ. So there is temporary paralysis of skeletal muscle Uses  Intubation of trachea and other endoscopic procedures  Induce muscle relaxation  Make orthopedic surgery easy and bone setting  Reduce dose of anesthesia  Used as adjuvant drug in surgical anesthesia 3

Types of Neuromuscular Blocking Drugs  Nondepolarizing drugs (competitive)  Depolarizing drugs (non-competitive)  Centrally acting drugs 4

1) Nondepolarizing (competitive) blocking agents Long acting: d-Tubocurarine, Pancuronium (steroidal nucleus) Doxacurium, Pipecuronium Intermediate acting: Atracurium, cis atracurium Vecuronium, Rocuronium Short acting: Mivacurium 5

2) Depolarizing agents (Non competitive) Suxamethonium (Succinylcholine) Decamethonium 3) Centrally acting Beclofenac Chlorzoxazone Diazepam cariosoprodol 6

Non-depolarizing/ Competitive (curare-like) Blocking agents N + (14 Å) N + GI resorption BBB 7

Curare is plant extract from Chondrodendron tomentosum, Strychnos toxifera etc. It is used by South America tribals as arrow poison for game hunting. The animals got pa- ralysed but not killed by the arrow. Muscle paralyzing active principles of curare are alkaloids tubocurarine, toxiferine etc. 8

N + : quarter- nary N-atom 9

Competitive (non-depolarizing) block  Most of the competitive blockers have two or more quaternary N + atoms which provide the necessary attraction to the same site at N receptor  And have long, flexible, bulky molecules and were termed Pachycurare by Bovet (1951)  The bulk groups of the drug molecule does not allow conformational changes in the subunits needed for opening the channel. 10

Mechanism of Action of Nondepolarizing/ competitive Neuromuscular Blocking Drugs Ach released from motor nerve endings is not able to combine with its N-receptors to generate end-plate potential (EPP). So contraction of muscle 11

 Intravenous injection of competitive blockers rapidly produces skeletal muscle weakness, followed by flaccid paralysis.  Small rapidly moving muscle fibers of eyes, ears toes are affected first making it impossible to perform delicate motor task and producing diplopia, slurred speech, and difficult in swallowing  spreads to hands, feet, arm, leg, neck, face, trunk, finally diapharm paralysed death due to hypoxia  Recovery occurs in the reverse sequence: diaphragmatic contractions resume first.  Increased histamine release from mast cells 12

Depolarizing drugs (non-competitive) 13

 Depolarizing agents also have two quaternary N + atoms but their molecule is long, slender, and flexible. They are termed Leptocurare by Bovet (1951)  Succinylcholine differ from Ach only in duration action, that is longer duration of action and more stable depolarization. 14

Depolarizing agents (Non competitive) MOA:  They depolarize muscle end-plates by opening Na + channels (just as ACh does) and initially produce twitching and fascilations.  These drugs do not dissociate rapidly from the receptor, induce prolonged partial depolarization of the region around muscle end-plate, and inactivation of Na + channels. 15

Synthesis of Succinyl Choline Dimer of Acetylcholine 16

Ganglion blocking agents - many side effecs - out of date 17

Ganglionic blockers  Ganglionic blockers inhibit autonomic activity by interfering with neurotransmission within autonomic ganglia.  This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility.  Reduced sympathetic output to the vasculature decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure.  Parasympathetic outflow is also reduced by ganglionic blockers. 18

Therapeutic Indications  Ganglionic blockers are not used in the treatment of in large part because of their side effects and because there are numerous, more effective, and safer antihypertensive drugs that can be used. They are, however, occasionally used for hypertensive emergencies. Specific Drugs  Several different ganglionic blockers are available for clinical use; however, only one (trimethaphan) is very occasionally used in hypertensive emergencies or for producing controlled hypotension during surgery. 19

Side Effects and Contraindications Side effects of trimethaphan include prolonged neuromuscular blockade potentiation of neuromuscular blocking agents. It can produce excessive hypotension and impotence due to its sympatholytic effect, and constipation, urinary retention, dry mouth due to it parasympatholytic effect. It also stimulates histamine release. 20