Anticholinergics 2 (1) PDF

CHOLINERGIC ANTAGONISTS LEARNING OBJECTIVES 1. Describe the mechanism of action of muscarinic cholinoreceptor antagonists 2. Describe the physiologic effects of muscarinic cholinoreceptor antagonists 3. List important therapeutic uses of muscarinic cholinoreceptor antagonists 4....

CHOLINERGIC ANTAGONISTS LEARNING OBJECTIVES 1. Describe the mechanism of action of muscarinic cholinoreceptor antagonists 2. Describe the physiologic effects of muscarinic cholinoreceptor antagonists 3. List important therapeutic uses of muscarinic cholinoreceptor antagonists 4. List the adverse effects and contraindications of muscarinic cholinoreceptor antagonists OVERVIEW OF ANTICHOLINERGICS  CHOLINERGIC ANTAGONISTS The cholinergic antagonists (cholinergic blockers or anticholinergic drugs) bind to cholinergic receptors, but they do not trigger the usual receptor-mediated intracellular effects They are divided into 2 major subgroups on the basis of their specific receptor affinities: Antimuscarinic (M receptor blockers), and Antinicotinic (Nicotinic receptor blockers) The antinicotinic drugs consist of Ganglionic stimulants & blockers Neuromuscular junction blockers (muscle relaxants) The most useful of these agents are the selective antimuscarinic agents of the parasympathetic nerves followed by the neuromuscular blocking agents The ganglionic blockers have little clinical usefulness – due to their diffuse or broad actions & lack of selectivity ANTIMUSCARINIC AGENTS Muscarinic antagonists are often called parasympatholytic because they block the effects of parasympathetic autonomic discharge; but the term "antimuscarinic" is preferable These agents competitively bind to the M cholinergic receptors – blocking ACh’s binding to these receptors, inhibiting its stimulatory effects In addition they block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary & sweat glands Unlike the cholinergic agonists (with limited therapeutic usefulness), the cholinergic blockers are beneficial in a variety of clinical situations Because they do not block N cholinergic receptors, they are devoid (or little) of both the skeletal neuromuscular junctions or autonomic ganglia effects ANTIMUSCARINIC AGENTS Scopolami Ipratropiu Atropine ne m Hyoscine- N- Other butylbromi de ATROPINE Atropine and its naturally occurring congeners are tertiary amine alkaloid esters of tropic acid Atropine (hyoscyamine) is found in the plant Atropa belladonna, and in Datura stramonium, also known as thorn apple At therapeutic doses atropine acts mainly peripherally, it has very low central effects (it does not cross the cross the BBB significantly) Tissues most sensitive to atropine are salivary, bronchial, & sweat glands. Secretion of acid by the gastric parietal cells is the least sensitive In general atropine has a duration of action of about 4 hours, but topically in the eye actions may last for days ATROPINE - MOA Atropine and related compounds have a higher affinity for M receptors They bind competitively to the common site on the cholinergic receptors blocking ACh and other cholinergic agonists from stimulating these receptors Since the binding of atropine to the M cholinergic receptors is competitive, it can be overcome if the concentration of ACh at the receptor sites is increased sufficiently Thus, blockade by atropine can be overcome by a larger concentration of: ACh (anti-ChE, like neostigmine) equivalent muscarinic agonist (bethanechol) Atropine is highly selective for M receptors; potency at N receptors is much lower Unfortunately it does not discriminate between the M1, M2, and M3 subgroups of muscarinic receptors ATROPINE – PHYSIOLOGICAL ACTIONS Eye Atropine blocks all cholinergic activity of the pupillary sphincter muscles of the iris and the ciliary muscles of the eye controlling lens curvature (M3 effects) resulting in persistent mydriasis (dilated pupil), unresponsiveness to light, cycloplegia (paralysis of the ciliary muscles of the eye), & inability to focus for near vision. The lens is fixed for far vision, near objects are blurred, and objects may appear smaller than they really are In patients with close-angle glaucoma, intraocular pressure may rise dangerously As a result short-acting agents, are generally favoured ATROPINE – PHYSIOLOGICAL ACTIONS GIT It has antispasmodic actions – reducing the activity of the GIT (M 3 effects) Atropine & scopolamine are probably the most potent drugs available that produce this effect It does not significantly reduce HCl production - not effective in promoting healing of peptic ulcer Pirenzepine & its potent analog telenzepine are selective M1-receptor antagonists – reduces gastric acid secretion at doses that do not antagonize other systems Histamine type-2 H2 receptor antagonists (cimetidine), and proton pump inhibitors (omeprazole) have replaced the nonselective muscarinic antagonists as inhibitors of acid secretion ATROPINE – PHYSIOLOGICAL ACTIONS Urinary system The antimuscarinic action of atropine relaxes smooth muscle of the ureter and bladder wall (M3 effects) and slows voiding It is employed clinically to reduce hypermotility states of the urinary bladder It is still occasionally used in enuresis (involuntary voiding of urine) among children, but α-adrenergic agonists with fewer side effects may be more effective ATROPINE – PHYSIOLOGICAL ACTIONS Secretions Atropine blocks the salivary glands, producing a drying effect on the oral mucus membranes (xerostomia) – since salivary glands are exquisitely sensitive to atropine (M3 effects) Sympathetically innervated sweat glands are also affected by small doses of atropine & scopolamine– suppressing thermoregulatory sweating, the skin becomes hot and dry Sweating may be depressed enough to raise the body temperature In adults, body temperature is elevated only at high doses of atropine - but in infants & children even ordinary doses may cause "atropine fever" ATROPINE – PHYSIOLOGICAL ACTIONS Respiratory system Both smooth muscle & secretory glands of the respiratory system are parasympathetically innervated and contain M receptors, but the anticholinergic effect is more significant in patients with airway diseases – but not as useful as the β2-AR stimulants in the treatment of asthma Atropine has limited effectiveness in treating chronic obstructive pulmonary disease (COPD) because it blocks auto-inhibitory M2 receptors on postganglionic presynaptic parasympathetic nerves endings This opposes the bronchodilation caused by blockade of M3 receptors on the effector smooth muscle (airway smooth muscle) ATROPINE – PHYSIOLOGICAL ACTIONS Cardiovascular Atropine produces varying effects on the cardiovascular system, depending on the dose At low doses - decreased cardiac rate (bradycardia) – this results from blockade of the autoregulatory M1 receptors on the inhibitory prejunctional neurons – permitting increased ACh release At higher doses - modestly increased cardiac rate (tachycardia) due to blockade of M2 receptors on the sinoatrial node. Arterial blood pressure is unaffected, because most vascular beds lack significant cholinergic innervation (peripheral vasodilation does occur – but there is no significant BP changes) At toxic levels – atropine will dilate the cutaneous vasculature ATROPINE – THERAPEUTIC INDICATIONS Ophthalmic Effect limited to the eye are obtained by administration of antimuscarinic agents locally in the eye The mydriatic & cycloplegic effects of atropine permits the measurement of refractive errors without interference by the accommodative capacity of the eye in conditions such as iridocyclitis (Inflammation of the iris and ciliary body) & keratitis (inflammation of the cornea) Mydriasis is often necessary for thorough examination of the retina & optic disc Homatropine (semisynthetic derivative of atropine), cyclopentolate, & tropicamide are other agents used in ophthalmology They are preferred to topical atropine because of their shorter duration of action They are also better tolerated ATROPINE – THERAPEUTIC INDICATIONS GIT Atropine is used as an antispasmodic agent to relax the GIT & bladder (rarely used for this purpose to date). Antimuscarinic agents are no longer used for the management of peptic ulcers They can reduce the secretion of gastric acid The anti-secretary dose produces pronounced adverse effects such as dry mouth, loss of visual accommodation, photophobia, & urinary retention Pirenzepine & its analog telenzepine have selectivity for M 1 over M2 and M3 receptors but their affinity for M1 & M4 receptors are comparable, as a result it does not possesses total M1 selectivity Both drugs are used in the treatment of peptic ulcer disease in some European countries, Japan, and Canada Pirenzepine produces about the same rate of healing of both duodenal and gastric ulcers as the H2 receptor antagonist's cimetidine & ranitidine (Zantac®) ATROPINE – THERAPEUTIC INDICATIONS Antidote for cholinergic agonists: Atropine (at high doses) is used for the treatment of overdoses of AChE inhibitors including those found in commercial insecticides & some types of mushroom poisoning. The antimuscarinic therapy does not affect the skeletal neuromuscular junction Antisecretory agent: Used to block secretions in the upper and lower respiratory tracts prior to surgery Anaesthesia Atropine or glycopyrrolate is used with neostigmine (to block the parasympathomimetic effects) when used to reverse the skeletal muscle relaxation after surgery. ATROPINE - PK Atropine is readily absorbed from the GIT & the conjuctival membrane and well distributed throughout the body including the CNS (limiting its tolerability when intended for peripheral effects) Partially metabolized by the liver with a plasma half-life (t1/2) of 2-4 hours The drug’s effects on the parasympathetic function declines rapidly in all organs – except in the eye About 60% of the dose is eliminated unchanged in the urine ATROPINE - A/E Poisoned individuals manifest as dry mouth, blurred vision, "sandy eyes," tachycardia, hot & flashed skin, urinary retention & constipation for as long as a week Body temperature is frequently elevated Effects on the CNS include restlessness, confusion, hallucinations, and delirium, which may progress to depression, collapse of the circulatory & respiratory systems, and death In older individuals, the use of atropine to induce mydriasis & cycloplegia is too risky, because it may exacerbate an attack of glaucoma SCOPOLAMINE Scopolamine is another belladonna alkaloid with peripheral effects similar to those of atropine However, scopolamine has greater action on the CNS & a longer duration of action in comparison to those of atropine  SCOPOLAMINE Physiological actions of scopolamine Marked central effects – at therapeutic dosages produces drowsiness & amnesia (loss of short- term memory) in sensitive individuals. In toxic doses, scopolamine (& to a lesser degree atropine) can cause excitement, agitation, hallucinations, and coma The tremor of Parkinson's disease is reduced by centrally acting antimuscarinic drugs Parkinsonian tremor & rigidity result from a relatively excessive cholinergic activity because of a deficiency of dopaminergic activity in the basal ganglia-striatum system The combination of an antimuscarinic agent with a dopamine precursor drug (Ievodopa) may provide more effective therapy than either drug alone Motion sickness appear to involve vestibular disturbances of the muscarinic cholinergic transmission Scopolamine is often effective in preventing or reversing these disturbances  SCOPOLAMINE Therapeutic uses of scopolamine Although similar to atropine, therapeutic use of scopolamine is limited to prevention of motion sickness (for which is particularly effective) and to block short-term memory As with all such drugs used for motion sickness, it is much more effective prophylactically than for treating motion sickness once it occurs The amnesic action of scopolamine makes it an important adjunct drug in anesthetic procedures Pharmacokinetics and Adverse effects Mostly similar to those seen with atropine, except scopolamine can be absorbed across the skin (transdermal route)  IPRATROPIUM (ATROVENT®) Ipratropium is a quaternary derivative of atropine & an antimuscarinic drug that is poorly absorbed orally It is also poorly distributed into the CNS – free of CNS effects Inhaled ipratropium and tiotropium (structural analog of ipratropium) is useful in treating asthma in patients who are unable to take b2-AR agonists or, in combination with β2-AR agonist to take advantage of the synergistic effect of the combination Inhaled ipratropium is also beneficial in the management of chronic obstructive pulmonary disease (COPD) COPD, also known as chronic obstructive airway disease (COAD), is a group of diseases characterised by the pathological limitation of airflow in the airway that is not fully reversible COPD is the general term for chronic bronchitis (inflammation of the bronchioles), emphysema (fluid in lung tissues) and a range of other lung disorders It is most often due to tobacco smoking but can be due to other airborne irritants such as coal dust, asbestos or solvents Because of ipratropium’s quaternary positive charge, it does not enter the systemic circulation nor the CNS HYOSCINE-N-BUTYLBROMIDE (SCOPEX®; BUSCOPAN®) Hyoscine-N-butylbromide is a structural analog of hyoscine Its use is limited for the treatment of GI spasms  OTHER ANTI-MUSCARINIC DRUGS Methscopolamine A quaternary ammonium derivative of scopolamine devoid of the CNS effects of scopolamine Its use is limited to mainly to GIT diseases (peptic ulcers & intestinal spasms) Homatropine methylbromide A quaternary derivative of homatropine which is less potent than atropine in its anti- muscarinic activities (but rather ganglionic blocking properties) Used in combination with hydrocodone as an antitussive combination. It has also been used to relief GIT spasms & as an adjunct in peptic ulcer disease Dicyclomine, flavoxate, trospium (quaternary ammonium compound), oxybutynin, & tolterodine are tertiary amines used for their antispasmodic properties At therapeutic doses, they decrease spasms of the GIT, bilary tract, & uterus  Ganglionic blockers specifically act on the N receptors of the autonomic ganglia Show NO selectivity for the parasympathetic or sympathetic GANGLIONI ganglia C Thus, they block the entire output of the ANS at the N receptor BLOCKERS Therefore, ganglionic blockade is rarely used therapeutically – often serve as tools in experimental pharmacology Ganglionic blockers are subdivided into 2 groups, i.e. Depolarising blockers – e.g. natural alkaloids nicotine & lobeline, carbamoylcholine & ACh (if amplified by AChE inhibitor), tetramethylammonium (TMA), dimethylphenylpiperazinium iodide (DMPP) Non-depolarising blockers – competitive neutral antagonists including trimethaphan, mecamylamine, hexamethonium, & tetraethylammonium (TEA) N cholinergic receptors of the ganglion (N N) & the skeletal muscle neuromuscular junction (NM) are subject to both depolarising & non-depolarising blockade  Depolarising blockade Depending on the dose, these agents bind to the NN cholinergic receptors first stimulating and then paralising GANGLIONI them Initial stimulation of the receptors gives rise to an initial C excitatory postsynaptic potential (EPSP) & depolarization of the ganglia due to the influx Na+ and sometimes Ca2+ BLOCKERS - through the neuronal type N-receptor channels MOA Then an action potential is generated in the postganglionic neuron following the attainment of the threshold potential (critical amplitude) from the initial EPSP The resultant effect is first stimulation Secondary paralysis occurs because – the depolarising agent remains attached to the receptor for a relatively longer time resulting in persistent depolarization and desensitization of the cholinergic receptors site and continued blockade Membrane repolarises but the continued binding desensitises the receptor – making it incapable of transmitting further impulses  Non-depolarising blockade The blockade of the autonomic ganglia produced by these agents does not involve prior ganglionic stimulation GANGLIONI They impair transmission either by: competing with ACh for the ganglionic N receptor (e.g. C trimethaphan), or BLOCKERS - blocking the ion channels (e.g. hexamethonium);this action shortens the duration of current flow because the open MOA channels becomes closed (clogged) In both the above mechanisms, the initial EPSP is blocked, and ganglionic transmission is inhibited Non-depolarizing competitive antagonists are the only once presently used as ganglion blockers clinically Hexamethonium produces most of its blockade by occupying sites in/ on the ion channel not by occupying the N receptor itself In contrast, trimethaphan & mecamylamine block the N receptor, not the channel Blockade can be at least partially overcome by increasing the concentration of the nicotinic cholinergic agonist like ACh DEPOLARISIN Nicotine was first isolated from the leaves G of tobacco, Nicotina tabacum by Poselt & GANGLIONIC Reiman in 1828 BLOCKERS - It is of considerable medical significance NICOTINE because of its toxicity, presence in tobacco, and ability to confer dependence to its users  Peripheral nervous system Small doses of nicotine stimulate the ganglion cells PHARMACOLOGICA directly and may facilitate impulse transmission L ACTIONS When large doses of the drug are administered, initial stimulation is followed very quickly by a blockade of transmission Nicotine possesses a biphasic action on the adrenal medulla: Small doses stimulates the discharge of catecholamines (NA, A) Large doses prevent their release in response to nerve stimulation Like ACh, Nicotine also stimulates sensory receptors of the tongue, lungs, stomach, thermal receptors of the skin and tongue, and pain receptors Pre-treatment with hexamethonium prevents the stimulation of these sensory receptors by nicotine  CNS (it markedly stimulates the CNS) Low doses produce week analgesia (pain relief) PHARMACOLOGICA and excitation of respiration L ACTIONS Higher doses produce respiratory depression, and death results from failure of respiration due to both central paralysis (medulla oblongata) and peripheral blockade of the muscles of respiration Nicotine induces vomiting by both central (chemoreceptor trigger zone in the area postrema of the medulla oblongata) and peripheral (vagal and spinal nerves involved in vomiting) actions Toxic levels of nicotine causes tremors and convulsion Chronic exposure to nicotine causes marked increase in density and number of N-cholinergic receptors – probably due to the compensatory response to the desensitization of receptor function by nicotine  Cardiovascular system IV administration of nicotine to laboratory animals PHARMACOLOGICA produces an increase in heart rate and BP L ACTIONS This response is due to stimulation of the sympathetic ganglia and adrenal medulla Also contributing to the sympathomimetic response to nicotine is the activation of the chemoreceptors of the aortic and carotid bodies – resulting in vasoconstriction, tachycardia, and elevated BP GIT The combined activation of the parasympathetic ganglia and cholinergic nerve endings by nicotine results in increased tone and motor activity of the bowel resulting in nausea, vomiting, and occasional diarrhea in nicotine naïve patients Exocrine glands Nicotine produces an initial stimulation of the salivary and bronchial secretions followed by inhibition  Absorption Nicotine is readily absorbed from the respiratory tract, buccal (directed toward the cheek) membranes, and skin PK Severe poisoning from nicotine has resulted from percutaneous (across the skin) absorption Nicotine is a strong base (pKa = 8.5) – its absorption from the stomach is limited, but intestinal absorption is far more efficient Nicotine in chewing tobacco has a longer duration of effect because of its slow absorption than the inhaled form The average cigarette contains 8-11 mg nicotine delivering 1-3 mg systemic nicotine to the smoker – bioavailability increase up to threefold with the intensity of puffing & technique of the smoker To obtain abstinence from tobacco use and help in preventing a withdrawal or a abstinence syndrome– nicotine is available in several dosage forms; i.e. orally as a gum (Nicorette®), transdermal patch (Nicoderm®), nasal spray (Nicotrol NS®), and vapour inhaler (Nicotrol inhaler®) The efficacy of these dosage forms in producing abstinence from smoking is enhanced by concurrent counselling and motivation therapy Fate and excretion Approximately 80-90% of absorbed nicotine is metabolised and transformed in the body mainly the liver, but also the kidney and lung Cotinine is the major metabolite, with nicotine-1’-N-oxide and 3-hydroxycotinine being found in lesser quantities The t1/2 = is 2 hours following inhalation or IV administration of nicotine Nicotine and its metabolites are rapidly eliminated by the kidney – the rate of urinary excretion is reduced when the urine in alkaline  The acutely fatal dose of nicotine for an adult in approximately 60 mg of the base ACUTE The absorption of oral nicotine is delayed because of slow gastric emptying – as a result vomiting caused by the initial absorbed nicotine on the CNS may NICOTINE remove much of the nicotine remaining in the GIT The rapid onset of acute nicotine poisoning may be in the form of nausea, POISONING salivation, abdominal pain, vomiting, diarrhoea, cold sweat, headache, dizziness, disturbed hearing and vision, mental confusion, and marked weakness BP drops; breathing is difficult; the pulse is weak, rapid, irregular; and collapse may be followed by terminal convulsions Death may result after few minutes due to respiratory failure Therapy Vomiting may be induced, or gastric lavage (a procedure used to empty the stomach of its contents Performed using a flexible rubber tube that is passed through the mouth and advanced to the stomach) should be performed. Alkaline solutions should be avoided Activated charcoal may be orally administered & respiratory assistance may be necessary NON- e.g. trimethaphan, mecamylamine, DEPOLARIZIN hexamethonium, tetraethylammonium G BLOCKERS  Cardiovascular system The blood vessels receive mainly vasoconstrictor fibers from the sympathetic division; therefore, ganglionic blockade causes ORGAN decrease in arteriolar & venous tone The BP may drop gradually due to decreased peripheral vascular SYSTEM resistance EFFECTS Since the sinoatrial node of the heart is usually dominated by the parasympathetic nervous system, a moderate tachycardia may occur following the gangionic blockade Other organ systems GIT - secretions are reduced (not enough to effectively treat peptic disease) & motility is profoundly inhibited & constipation may be serious Genitourinary smooth muscles - partially dependent on autonomic innervation for normal function Ganglionic blockade therefore may precipitate urinary retention in men with prostatic hyperplasia (enlarged prostate) Sexual functions - are impaired in that both erection & ejaculation Thermoregulatory sweating is blocked by the ganglion-blocking drugs CLINICAL Because of the increasing availability of APPLICATION selective autonomic blocking agents, ganglionic blockers are rarely used to date S Mecamylamine: studied for possible use in reducing nicotine craving Used for the treatment of moderately to severe hypertension Also used as an alternative therapy for hypertensive crises Trimethaphan: occasionally used in the treatment of hypertensive crises  NEUROMUSCULAR BLOCKING DRUGS These drugs block cholinergic transmission between motor nerve endings of the somatic division & the N receptors on the neuromuscular end plate of skeletal muscle (muscle relaxants) These neuromuscular blockers are structural analogs of ACh, and are either: Nondepolarising (competitive) blockers, or Depolarizing blockers They are useful clinically during surgery to produce complete muscle relaxation A 2nd group of muscle relaxants are centrally acting and useful in controlling spastic muscle tone - Diazepam & baclofen, which binds GABA receptors Thirdly dantrolene and botolinum toxin act peripheraly - dantrolene interferes with the release of Ca2+ from the sarcoplasmic reticulum directly on muscle NONDEPOLARISING (COMPETITIVE) BLOCKERS The 1st drug that was found to be capable of blocking the skeletal neuromuscular junction was curare (from the Strychnos spp) Curare is a generic term for various South American arrow poisons which the native hunters of the Amazon in South America used to paralyze their prey The modern clinical application of curare dates from 1932 when the highly purified fraction was used in patients with tetanus and spastic disorders. The drug tubocurarine was ultimately purified from curare, synthesised, & introduced into clinical practice in the early 1940s. Then structural modifications of tubocurarine where made, and this led to the development of other non- depolarising neuromuscular blocker Other members of this group include; atracurium, cisatracurium, doxacurium, metocurine, mivacurium, pancuronium, rocuronium, pipecurium & vecuronium The neuromuscular blocking agents have significantly increased the safety of anesthesia because less anesthetic is required to produce muscle relaxation MOA – NON-DEPOLARIZING MUSCLE RELAXANTS At low doses Competitive blockers bind to the N cholinergic receptor (especially the NM) at the end plate, thereby competitively blocking the binding of ACh preventing depolarisation of the muscle cell membrane & inhibit muscular contraction. Their action can be overcome by increasing the concentration of ACh in the synaptic gap At high doses Can block the ion channels of the end plate. This leads to further weakening of neuromuscular transmission & reduced ability of AChE inhibitors to reverse the actions of non-depolarising muscle relaxants  PHARMCOLOGICAL ACTIONS – NON- DEPOLARIZING MUSCLE RELAXANTS Sequence and characteristics of paralysis: Not all muscles are equally sensitive to blockade by competitive blockers. Muscles of the face and eye are most susceptible & are paralyzed 1 st, followed by the jaw and the larynx. Then muscles of the limbs, neck, trunk, and the intercostal muscles are affected. Lastly, the diaphragm muscles are paralyzed and respiration then ceases Recovery of muscle usually occurs in the reverse order to that of the paralysis – thus the diaphragm ordinarily is the 1 st muscle to regain function Histamine release: Tubocurarine produces typical histamine-like wheals following intracutaneous or intra-arterial injection in human. It also produces other histamine-like effects such as bronchospasms, hypotension, excessive bronchial and salivary secretions. All the above effects appear to be caused by the release of histamine triggered by tubocurarine Mivacurium, atracurium, succinylcholine, and doxacurium also trigger the release histamine – but to a lesser extent unless administered rapidly The histamine release is a direct action of the muscle relaxant on the mast cells – not the IGE-mediated anaphylaxis. Autonomic ganglia and muscarinic sites: Neuromuscular blocking agents show variable potencies in producing ganglionic blockade. At therapeutic doses, tubocurarine is the least selective in this group of agents followed by pancuronium. The others are more selective for the motor end plate. Pancuronium has a vagolytic action, presumably from blockade of muscarinic cholinergic receptors – that leads to tachycardia THERAPEUTIC USES These blockers are mainly used therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle Muscle relaxation is also of value in various orthopedic procedures – such as the correction of dislocations and alignment of fractures Short acting neuromuscular blockers are used in combination with generalised anaesthetics to facilitate intubation of an endotracheal tube in laryngoscopy, bronchoscopy, and esophagoscopy These agents are also used in psychiatry to prevent trauma during electroconvulsive therapy (ECT) – seizures induced may cause dislocation of fractures Control of muscle spasms – botulinum toxins are preferred PK All neuromuscular blocking agents are injected IV – due to their minimal uptake via oral route They penetrate membranes very poorly & do not enter cells or cross the BBB Tubocurarine, pancuronium, mivacurium, metocurine, & doxacurium are excreted in the urine unchanged Atracurium is degraded spontaneously in the plasma and by ester hydrolysis Atracurium has been replaced by its isomer, cisatracurium since atracurium releases histamine & is metabolized to laudanosine, which can provoke seizures Vecuronium and rocuronium are deacetylated in the liver, and their clearance may be prolonged in patients with hepatic disease DRUG INTERACTIONS Cholinesterase Inhibitors E.g. neostigmine & edrophonium can overcome the action of nondepolarizing neuromuscular blockers but with increased dosage, AChE inhibitors can cause a depolarising block as a result of elevated ACh levels at the end-plate membrane Halogenated hydrocarbon anesthetics Drugs such as halothane act to enhance neuromuscular blockade by exerting a stabilizing action at the neuromuscular junction Aminoglycosides antibiotics E.g. gentamicin or tobramycin inhibit ACh release from cholinergic nerves by interfering with Ca2+ ions conduction enhancing the blockade Ca2+-channel blockers These agents may increase the neuromuscular block of tubocurarine & other competitive blockers as well as depolarizing blockers DEPOLARISING NEUROMUSCULAR BLOCKERS Succinylcholine is the sole member in this group that is available for systemic use in humans Decamethonium also possesses the actions of a depolarising blocker  MOA Succinylcholine binds to the N cholinergic receptor of the motor end plate & mimic the actions of ACh depolarising the junction Unlike ACh, the depolarising agent persists at high levels in the synaptic cleft for a relatively longer time providing a constant stimulation The depolarizing agent 1st causes the opening of the Na+ channel associated with the N receptors resulting in depolarisation of the receptor- an initial excitatory postsynaptic potential (EPSP) (Phase I) This leads to a transient twitching of the muscle due to the release of Ca 2+ from the sarcoplasmic reticulum The continued binding of the depolarising agent desensitises the receptors (rendering them incapable of transmitting further impulses) Even though the receptor is gradually repolarized as the Na + channel closes – the resultant effect is resistance to further depolarization (Phase II) & a flaccid (lacking firmness) paralysis  PHARMACOLOGICAL ACTIONS The sequence of paralysis may be slightly different - but like competitive blockers, the respiratory muscles are paralyzed last Succinylcholine initially produces short-lasting muscle contractions, followed within a few minutes by paralysis The drug does not produce a ganglionic block except in high doses – but it also triggers histamine release Normally, the duration of action of succinylcholine is extremely short, because this drug is rapidly broken down by both plasma and hepatic cholinesterase (BuChE) to almost undetectable levels Malignant hyperthermia (heatstroke) Malignant hyperthermia can manifest by elevated body temperature, lack of sweating, hot dry skin, and neurologic symptoms (such as unconsciousness, paralysis, headache, vertigo, confusion) It is a potentially life-threatening event triggered by the administration of certain anaesthetics and neuromuscular blocking agents The initiating event is the uncontrolled release of Ca2+ from the sarcoplasmic reticulum of the skeletal muscles Other clinical features include contracture, rigidity, and heat production from the skeletal muscles resulting in severe hyperthemia, accelerated muscle metabolism, metabolic acidosis, and tachycardia Halogenated hydrocarbon anaesthetics (like halothane, isoflurane, & sevoflurane) and succinylcholine OR the combination of these agents has been associated with incidents of malignant hyperthermia Treatment entails the administration of dantrolene, which blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells thus reducing heat production & relaxing muscle tone Rapidly cooling of the patient, inhalation of 100% oxygen, and control of acidosis should be considered adjunct therapy in malignant hyperthermia  T/I, PK, A/E Therapeutic uses Because of its rapid onset and short duration of action, succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia a rapid action is essential if aspiration of gastric contents is to be avoided during intubation It is also employed during electroconvulsive shock therapy Pharmacokinetics Succinylcholine is injected intravenously Its brief duration of action (several minutes) results from redistribution & rapid hydrolysis by plasma cholinesterase It therefore is usually given by continuous infusion Adverse effects Hyperthermia: Already explained Apnoea (temporary cessation of breathing): Apnoea due to paralysis of the diaphragm Especially in patient who is genetically deficient in plasma cholinesterase  Poisoning occurs especially in rural communities where; the use of cholinesterase inhibitor (organophosphate) insecticides is common, & cultures where wild mushrooms are commonly eaten Mushroom poisoning is divided into rapid-onset and delayed-onset types The rapid onset type appears within 15-30 minutes of ingestion of the mushrooms characterised entirely by signs of muscarinic excess: N, V, & D, vasodilation, reflex tachycardia, sweating, salivation, & sometimes bronchoconstriction Amanita muscaria contains muscarine & numerous other alkaloids, including CHOLINERGIC antimuscarinic agents. In fact, ingestion of A muscaria may produce signs of atropine poisoning, not POISONING muscarine. Delayed-onset types Other forms of mushroom poisoning manifests its 1st symptoms 6-12 hours after ingestion E.g. Amanita phalloitks, A. virosa, Galnina autumnalis, or G. marginata,. Although the initial symptoms usually include nausea and vomiting, the major toxicity involves hepatic and renal cellular injury by amatoxins that inhibit RNA polymerase Atropine is of no value in this form of mushroom poisoning Application of organophosphates as chemical warfare "nerve gases" also requires an awareness of the methods for treating acute poisoning  Antimuscarinic agents TREATMENT Cholinesterase regenerator compounds OF Reversible inhibitors of the AChE to prevent CHOLINERGIC binding to the irreversible organophosphate – via competition POISONING Symptomatic treatment  Antimuscarinic therapy Both the N and the M effects of the AChE inhibitors can be life- threatening There is no effective method for directly blocking the nicotinic effects of AChE inhibition - because N agonists & blockers cause blockade of the entire autonomic transmission tertiary amine drug preferably atropine must be used to treat both the CNS & PNS effects of the organophosphate inhibitors Large doses of atropine may be needed to combat the muscarinic effects of extremely potent agents like parathion & TREATMENT OF chemical warfare nerve gases: 1-2 mg of atropine sulfate may be given IV every 5-15 minutes CHOLINERGIC until signs of effect (dry mouth, reversal of miosis) appear Treatment may be as long as 1 month for full control of POISONING muscarinic actions Reversible inhibitors of the enzyme Pretreatment with reversible inhibitors of AChE to competitively prevent binding of the irreversible organophosphate inhibitor This prophylaxis can be achieved with pyridostigmine or physostigmine Reserved for situations in which possible lethal poisoning is anticipated, eg, chemical warfare  Cholinesterase regenerator compounds Members of these group of agents include oxime agents such as pralidoxime (PAM), diacetylmonoxime (DAM) Mechanism of action The oxime group (-NOH) has a very high affinity for the phosphorus atom, & these drugs are able to hydrolyse the phosphorylated enzyme if the complex has not "aged" Pralidoxime (clinically applicable) is most effective in regenerating the cholinesterase associated with skeletal muscle neuromuscular junctions Because of its positive charge, it does not enter the CNS & is CHOLINESTERA ineffective in reversing the central effects of organophosphate SE poisoning. Diacetylmonoxime (clinical trials), on the other hand, does cross REGENERATORS the BBB & can regenerate some of the central nervous system cholinesterase Pharmacokinetics Pralidoxime is administered by intravenous infusion 1,-2 g given over 15-30 minutes. Even after aging of the phosphate-enzyme complex, multiple doses of pralidoxime over several days may still be useful in severe poisoning Pralidoxime is not recommended for the reversal of inhibition of