Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
NMDA receptor wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
DEPOLARIZING NEUROMUSCULARBLOCKING DRUGS Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statisticsPhD ( physiology), IDRA but In 1942 was DTC • Succinylcholine, introduced by Thesleff and Foldes and colleagues in 1952, • changed anesthetic practice drastically. • Its rapid onset of effect and ultra short duration of action permitted rapid endotracheal intubation • quaternary ammonium compound • comparable to two molecules of acetylcholine linked together Decamethonium went out of use Water soluble Six methyl groups – suxa methonium Basic chemistry • Positive charges at these sites in the molecules mimic the quaternary nitrogen atom of the transmitter acetylcholine and are the principal reason for the attraction of these drugs to muscleand neuronal-type nAChRs at the neuromuscular junction. Ach receptors • These receptors are also located at other physiologic sites of acetylcholine in the body, such as the neuronal-type nicotinic receptors in autonomic ganglia and as many as five different muscarinic receptors on both the parasympathetic and sympathetic sides of the autonomic nervous system Mechanism • The depolarising muscle relaxants act in the same way as ACh. • They act by attaching on the same binding site of ACh on the α-subunit of nicotinic receptor to open the receptor channel and initiates depolarisation. Acetyl choline and scoline • • • • Sodium channel has two gates Voltage gated and time gated Time gate – open Depolarization – voltage gated opens and na flows depolarization occurs • Time gate closes after 1 -2 millisecond • It can open only if voltage gate closes • Acetyl choline destroyed - VG closes - Time gate opens but in scoline – continuos depolarization VG opens continuosly –s o time gate never opens Scoline Scoline – again !! VG TG • Depolarization opens Na channel • Voltage gated (VG) opens • Na flows. • Time gated(TG) – closes • It does not open until VG closes • Depolarization – relaxation Pictures taken and modified from internet for closed academic purpose only Accommodation • a further burst of acetylcholine from the nerve terminal cannot produce depolarisation of end plate due to the still presence of succinylcholine at the end plate and can not overcome the inactivated state of Na+ channel in perijunctional area due to continuous depolarisation of end plate. • So, neuromuscular transmission is blocked Fasciculation • Succinylcholine also has presynaptic action. • Binding of succinylcholine to this presynaptic nicotine receptors depolarises the nerve terminals • action potential may be generated which travel backwards retrogradely along the nerve terminals to invade the neighbouring branches and thus produce contraction of a whole motor unit. Extra ocular and IOP rise • Multiple receptors • Special receptor which does not cause to paralyse with scoline • Hence sustained contraction may occur DPs and NDPs • Stimulate Ach receptors like Ach , persistent – time gate – paralysis • Scoline • Competitively antagonize Ach receptors vecuronium Pharmacokinetics • • • • • • • • • Dose is 1 mg / kg – intravenous --but IM 4 mg Ideal body weight Fasciculation in 30 seconds Usually complete relaxation in 60 seconds Duration 5 – 10 minutes Lot of studies prove 0.6 mg /kg is enough Higher the dose , may not increase duration 2.5 mg/min IV infusion Rapid and profound relaxation for a short duration So low dose NDPs decrease fasciculation • Binding of succinylcholine to this presynaptic nicotine receptors depolarises the nerve terminals and action potential may be generated which travel backwards retrogradely along the nerve terminals to invade the neighbouring branches and thus produce contraction of a whole motor unit • Fasciculation !! Not like nondepolarizers • Succinylcholine produces a characteristic depolarizing block that is associated with the absence of fade in response to train-of-four and tetanic stimulations, the absence of post- tetanic facilitation, and increased block in the presence of anticholinesterase drugs • The transition from a depolarizing to a phase II block is gradual and usually occurs after administration of 7-10mg/ kg of succinyl choline. • The recovery from a phase II block is much slower. Phase I block • Muscle fasciculation preceding the onset of neuromuscular blockade • Absence of post tetanic potentiation • Lack of fade to frequent stimulation (eg, tetanus, train of four, or double burst) • Block antagonized by nondepolarizing drugs • Block potentiated by acetylcholinesterase inhibitors Phase II block ( Dual block ) • Absence of muscle fasciculation • Presence of post tetanic potentiation • Fade with frequent stimulation • Possible synergism between various groups of non depolarizing relaxants • Phase II block and non depolarizing block potentiate each other • Block may be reversed by acetylcholinesterase inhibitors Phase II block • Duration - more than ten minutes • Dosage more than 10 mg/kg • Agents prolonged exposure of the neuromuscular junction to SCh, there is a conformational change at the receptors Phase II block drug itself enter into the channel to obstruct it, and pass through the channel into the cytoplasm like open and close channel blockade. Dual block • • • • Phase A – depolarizing – 30 minutes Phase B – non depolarizing block – develops Phase C – persistence – 30 minutes Phase D – wearing off – 2 hours • Can we reverse ?? • Controversial – can be done It gets metabolized as such Repeat dose – bradycardia Presynaptic , NMJ and extrajunctional Muscle pains • Middle age , females – more • First day but may be in fourth day also • Fasciculations , Muscle lactic acid and increased muscle potassium –reasons • Less frequent in muscular persons and slow injection • But can we give slow ? Already only a fraction of the given dose reaches the NM junction – slow means ?? • occurs in unusual sites, such as the diaphragm, intercostal muscles and between the scapulae • Children elderly and pregnant – less incidence • Interval between thio and scoline – more the incidence • Sore throat – is it muscle pain or tube ? Prevent myalgias • Low dose non depolarizers pretreatment • ? Atracurium • Preop stretching, magnesium , phenytoin, vitamin C , dantrolene, NSAIDs • Iv lignocaine 2 mg / kg • Give scoline 10 mg – wait and then give rest • Self pretreatment Side effects of SCh • Hyperkalemia In normal patients, the depolarization induced by SCh administration causes an increase in serum potassium level of 0.5 to 1.0 mEq/L. • burns, massive tissue trauma, disuse OK atrophy, hemiparesis, spinal cord trauma, and neuromuscular disorders (eg, Guillain-Barré disease, amyotrophic lateral sclerosis, Friedreich ataxia Three days to three months • (1) loss of motor nerve control over motor endplates that results in a proliferation of extrajunctional receptors, • (2) damaged muscle membranes, • (3) defective muscle membranes in certain muscle diseases. • In the acutely injured state, the critically dangerous period begins after a grace period of 48 to 72 hours. Kids ? • Marked hyperkalemia may also give rise to cardiovascular effects • Pretreatments given to attenuate the muscle pains also attenuate the increase in plasma potassium to a certain extent. • Avoid • Hyperkalaemia after succinylcholine has also been reported, albeit rarely, in patients with widespread intra-abdominal infection, severe trauma and closed head injury. • Mind it – not sickle cell Sick cell syndrome • SCh can increase the intraocular pressure (IOP) • Increased IOP reaches a maximum approximately 2 minutes after SCh is administered and disappears in approximately 6 minutes • Acute eye injuries – really want scoline – precurarize and go deep before intubation Clinical relevance ?? • Increased intragastric pressure of approximately 40 cm H2O occurs after scoline • blunted by pretreatment using a NDP drug and a larger dose of SCh (1.5 mg/kg) to achieve good intubating conditions • GE sphincter also contracts – no problem • In hiatus hernia ? ICT • Increased intracranial pressure can occur via muscle fasciculations, creating a venous pressure elevation in epidural and jugular veins, and through increased cerebral blood flow • Pretreatment with NDPs • Don’t allow insufficient anesthesia and hypercapnia • The direct vagal effect (muscarinic) produces sinus bradycardia, especially in patients with high vagal tone, such as children and the physically fit. • Repeat doses – dangerous • Glyco or atropine Pretreatment • Nodal rythms Masseter • Administration of succinylcholine has been observed to give rise to masseter muscle spasm. This may be severe in some patients, making laryngoscopy and intubation difficult • Harbinger of malignant hyperthermia !! scoline apnea • Stop breathing • Operation over ! Wake up ??! • little effort to cough or breathe • The pulse rate and blood pressure rise. • Patients may sweat and the pupils may dilate. This occurs because the patient becoming aware but is still paralysed. • Inherited reductions in butyrylcholinesterase activity occur because of mutations at a single autosomal location on the long arm of chromosome 3. • Physiologic reductions may occur with extremes of age and during pregnancy. • reduced availability of the enzyme in the presence of other substrates (e.g. etomidate, methotrexate and esmolol). • ester local anaesthetics, Some more causes • Causes of reduced plasma cholinesterase activity include reduced enzyme synthesis (e.g. liver disease, carcinomatosis, starvation and renal disease); enzyme inhibition by other drugs (e.g. neostigmine, organophosphorus compounds and metoclopramide); • plasma cholinesterase activity as low as 150 u litre (normal range 677--1,560) did not cause the clinical duration of succinylcholine to exceed 22min. Dibucaine • Plasma cholinesterase also named- butyryl cholinesterase • Butyryl choline intravenously, the enzyme converts it to the products butyric acid and choline. • it hydrolyses succinylcholine, in two stages to succinyl monocholine and choline, then to succinic acid and a second molecule of choline. • Dibucaine inhibits normal butyrylcholinesterase activity, reducing the ability to convert butyrylcholine to its byproducts Dibucaine number • Plasma + benzoyl choline – light emitted • Percentage of plasma cholinesterase inhibited by 10 -5 molar solution dibucaine • Normal is 75 – 85 • E uE u • EaE u • EaEa • Ef • Es Taken from the internet and books for closed academic purpose only Scoline apnea • • • • IPPV and sedation Send blood for cholinesterase level Fresh blood FFP Vaisiya chettiyarcommunity prone • And wait for apnea • post-operative care of patient and families • Suxamethonium apnea in a 72 year old Case report – • Any non depolarizer with metabolism by plasma cholinesterase • Innumerable problems with scoline but the ideal drug for RSI and laryngospasm • But with the onslaught of rocuronium and suggamadex -- ? • Is it not the time to stop the use of Scoline® (suxamethonium chloride) for rapid sequence intubation? Summary • • • • • • • Structure, chemistry Dose- pharmacokinetics Pharmacodynamics and mechanism Dual block Advantage Side effects Scoline apnea