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| Parasympathetic preganglionic arise from | 3 7 9 10 s2 to s4 90% by vagus |
| A. Acetylcholine | Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes. Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it lacks therapeutic importance because of its multiplicity of actions (leading to diff use effects) and its rapid inactivation by the cholinesterases. ACh has both muscarinic and nicotinic activity. |
| Acetylcholine action on heart rate and cardiac output | 1. Decrease in heart rate and cardiac output: The actions of ACh on the heart mimic the effects of vagal stimulation. For example, if injected intravenously, ACh produces a brief decrease in cardiac rate (negative chronotropy) and stroke volume as a result of a reduction in the rate of firing at the sinoatrial (SA) node. [Note: It should be remembered that normal vagal activity regulates the heart by the release of ACh at the SA node.] |
| Acetylcholine on blood pressure | 2. Decrease in blood pressure: Injection of ACh causes vasodilation and lowering of blood pressure by an indirect mechanism of action. ACh activates M3 receptors found on endothelial cells lining the smooth muscles of blood vessels. This results in the production of nitric oxide from arginine [also known as endothelium-derived relaxing factor.]NO then diff uses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and smooth muscle relaxation via phosphodisterase-3 inhibition. In the absence of administered cholinergic agents, the vascular receptors have no known function, because ACh is never released into the blood in any significant quantities. Atropine blocks these muscarinic receptors and prevents ACh from producing vasodilation. |
| Other actions of acetylchline | In the gastrointestinal (GI) tract, acetylcholine increases salivary secretion and stimulates intestinal secretions and motility. It also enhances bronchiolar secretions. In the genitourinary tract, ACh increases the tone of the detrusor urinae muscle, causing expulsion of urine. In the eye, ACh is involved in stimulating ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle, causing miosis (marked constriction of the pupil). ACh (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery. |
| B. Bethanechol | Bethanechol is an unsubstituted carbamoyl ester, structurally related to ACh, in which the acetate is replaced by carbamate, and the choline is methylated. Hence, it is not hydrolyzed by AChE (due to the esterifi cation of carbamic acid), although it is inactivated through hydrolysis by other esterases. It lacks nicotinic actions (due to the addition of the methyl group) but does have strong muscarinic activity. Its major actions are on the smooth musculature of the bladder and GI tract. It has about a 1-hour duration of action. |
| 1. Actions: Bethanechol | 1. Actions: Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone. It also stimulates the detrusor muscle of the bladder, whereas the trigone and sphincter are relaxed. These effects increase voiding pressure and decrease bladder capacity to cause expulsion of urine. Activates muscarinic (M) receptors and increases IP3 and DAG |
| Bethanechol Therapeutic applications: | 2. Therapeutic applications: In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly in postpartum or postoperative, nonobstructive urinary retention. Bethanechol may also be used to treat neurogenic atony as well as megacolon.Bladder and bowel atony, for example, after surgery or spinal cord injury |
| Adverse effects: Bethanechol | 3. Adverse effects: Bethanechol causes the effects of generalized cholinergic stimulation-. These include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm. Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to this agent.cyclospasm urinary urgency, plus vasodilation, reflex tachycardia, and sweating |
| C. Carbachol (carbamylcholine) | Carbachol has both muscarinic as well as nicotinic actions. It lacks the methyl group present in bethanechol. Like bethanechol, carbachol is an ester of carbamic acid and a poor substrate for AChE. It is biotransformed by other esterases but at a much slower rate. |
| 1. Actions: Carbachol | 1. Actions: Carbachol has profound effects on both the cardiovascular and GI systems because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems. It can cause release of epinephrine from the adrenal medulla by its nicotinic action. Locally instilled into the eye, it mimics the effects of ACh, causing miosis and a spasm of accommodation in which the ciliary muscle of the eye remains in a constant state of contraction. |
| Carbachol 2. Therapeutic uses: | 2. Therapeutic uses: Because of its high potency, receptor nonselectivity, and relatively long duration of action, carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma by causing pupillary contraction and a decrease in intraocular pressure. Onset of action for miosis is 10 to 20 minutes. Intraocular pressure is reduced for 4 to 8 hours. |
| Carbachol 3. Adverse effects: | 3. Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration (quaternary amine). |
| D. Pilocarpine | The alkaloid pilocarpine is a tertiary amine and is stable to hydrolysis by AChE. Compared with ACh and its derivatives, it is far less potent but is uncharged and will penetrate the CNS at therapeutic doses. Pilocarpine exhibits muscarinic activity and is used primarily in ophthalmology.Activates muscarinic (M) receptors • increases IP3 and DAG may also activate EPSP via M receptors in ganglia |
| Pilocarpine 1. Actions: | 1. Actions: Applied topically to the cornea, pilocarpine produces rapi miosis and contraction of the ciliary muscle. When the eye undergoes this miosis, it experiences a spasm of accommodation. The vision becomes fixed at some particular distance, making it impossible to focus.Pilocarpine is one of the most potent stimulators of secretions (secretagogue) such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. The drug is beneficial in promoting salivation in patients with xerostomia resulting from irradiation of the head and neck. Sjögren’s syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpine tablets and cevimeline, a cholinergic drug that also has the drawback of being nonspecific |
| Pilocarpine 2. Therapeutic use | 2. Therapeutic use in glaucoma: Pilocarpine is used to treat glaucoma and is the drug of choice in the emergency lowering of intraocular pressure of both narrow-angle (or closed-angle) and wide-angle (also called open-angle) glaucoma. Pilocarpine is extremely effective in opening the trabecular meshwork around Schlemm’s canal, causing an immediate drop in intraocular pressure as a result of the increased drainage of aqueous humor. This action occurs within a few minutes, lasts 4 to 8 hours, and can be repeated. The organophosphate echothiophate inhibits AChE and exerts the same effect for a longer duration. [Note: Carbonic anhydrase inhibitors, such as acetazolamide, as well as the β-adrenergic blocker timolol, are effective in treating chronic glaucoma but are not used for emergency lowering of intraocular pressure.] The miotic action of pilocarpine is also useful in reversing mydriasis due to atropine.Sjögren’s syndrome (increases salivation) • was used in glaucoma (causes miosis, cyclospasm |
| 3. Adverse effects: Pilocarpine | 3. Adverse effects: Pilocarpine can enter the brain and cause CNS disturbances. Poisoning with this agent is characterized by exaggeration of various parasympathetic effects, including profuse sweating (diaphoresis) and salivation. The effects are similar to those produced by consumption of mushrooms of the genus Inocybe. Parenteral atropine, at doses that can cross the blood-brain barrier, is administered to counteract the toxicity of pilocarpine. cyclospasm, diarrhea, urinary urgency, plus vasoconstriction , reflex tachycardia |
| . Edrophonium | Edrophonium is the prototype short-acting AChE inhibitor. Edrophonium binds reversibly to the active center of AChE, preventing hydrolysis of ACh. It is rapidly absorbed and has a short duration of action of 10 to 20 minutes due to rapid renal elimination. Edrophonium is a quaternary amine, and its actions are limited to the periphery. |
| . Edrophonium use and adverse | It is used in the diagnosis of myasthenia gravis, which is an autoimmune disease caused by antibodies to the nicotinic receptor at NMJs. This causes their degradation, making fewer receptors available for interaction with the neurotransmitter. Intravenous injection of edrophonium leads to a rapid increase in muscle strength. Care must be taken, because excess drug may provoke a cholinergic crisis (atropine is the antidote). Increased parasympathetic effects, especially nausea, vomiting, diarrhea, urinary urgency. Edrophonium may also be used to assess cholinesterase inhibitor therapy, for differentiating cholinergic and myasthenic crises, and for reversing the effects of nondepolarizing neuromuscular blockers after surgery. Due to the availability of other agents, edrophonium use has become limited. |
| B. Physostigmine | Physostigmine is a nitrogenous carbamic acid ester found naturally in plants and is a tertiary amine. It is a substrate for AChE, and it forms a relatively stable carbamoylated intermediate with the enzyme, which then becomes reversibly inactivated. The result is potentiation of cholinergic activity throughout the body. |
| 1. Actions: Physostigmine | 1. Actions: Physostigmine has a wide range of effects as a result of its action, and stimulates not only the muscarinic and nicotinic sites of the ANS but also the nicotinic receptors of the NMJ. Its duration of action is about 2 to 4 hours, and it is considered to be an intermediate-acting agent. Physostigmine can enter and stimulate the cholinergic sites in the CNS. |
| Physostigmine 2. Therapeutic uses: | 2. Therapeutic uses: The drug increases intestinal and bladder motility, which serve as its therapeutic action in atony of either organ. Placed topically in the eye, it produces miosis and spasm of accommodation, as well as a lowering of intraocular pressure. It is used to treat glaucoma, but pilocarpine is more effective. Physostigmine is also used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine, phenothiazines, and tricyclic antidepressants. |
| Physostigmine 3. Adverse effects: | 3. Adverse effects: The effects of physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia and a fall in cardiac output may also occur. Inhibition of AChE at the skeletal NMJ causes the accumulation of ACh and, ultimately, results in paralysis of skeletal muscle. However, these effects are rarely seen with therapeutic doses. |
| C. Neostigmine | Neostigmine is a synthetic compound that is also a carbamic acid ester, and it reversibly inhibits AChE in a manner similar to that of physostigmine. |
| Neostigmine 1. Actions: | Unlike physostigmine, neostigmine has a quaternary nitrogen. Therefore, it is more polar, is absorbed poorly from the GI tract, and does not enter the CNS. Its effect on skeletal muscle is greater than that of physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has an intermediate duration of action, usually 30 minutes to 2 hours. |
| Neostigmine theraupetic affects | It is used to stimulate the bladder and GI tract, as an antidote for tubocurarine and other competitive neuromuscular blocking agents. Neostigmine is also used symptomatically to treat myasthenia gravis. Neostigmine and other AChE inhibitors preserve endogenous ACh, which can stimulate a greater number of ACh receptors at the muscle endplate. |
| Neostigmine 3. Adverse effects: | Adverse effects of neostigmine include those of generalized cholinergic stimulation, such as salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm Increased parasympathetic effects, especially nausea, vomiting, urinary urgency. Neostigmine does not cause CNS side effects and is not used to overcome toxicity of central-acting antimuscarinic agents such as atropine. Neostigmine is contraindicated when intestinal or urinary bladder obstruction is present. It should not be used for patients who have peritonitis or inflammatory bowel disease |
| D. Pyridostigmine and ambenonium | Pyridostigmine and ambenonium are other cholinesterase inhibitors that are used in the chronic management of myasthenia gravis. Their durations of action are intermediate (3 to 6 hours and 4 to 8 hours, respectively), but longer than that of neostigmine. Adverse effects of these agents are similar to those of neostigmine. |
| E. Tacrine, donepezil, rivastigmine, and galantamine | As mentioned above, patients with Alzheimer disease have a deficiency of cholinergic neurons in the CNS. This observation led to the development of anticholinesterases as possible remedies for the loss of cognitive function. Tacrine was the first to become available, but it has been replaced by others because of its hepatotoxicity. Despite the ability of donepezil, rivastigmine, and galantamine to delay the progression of Alzheimer disease, none can stop its progression. GI distress is their primary adverse effect. |
| ANTICHOLINESTERASES (IRREVERSIBLE) | A number of synthetic organophosphate compounds have the capacity to bind covalently to AChE. The result is a long-lasting increase in ACh at all sites where it is released. Many of these drugs are extremely toxic and were developed by the military as nerve agents. Related compounds, such as parathion, are used as insecticides. |
| 1. Mechanism of action: Echothiophate | 1. Mechanism of action: Echothiophate is an organophosphate that covalently binds via its phosphate group to the serine-OH group at the active site of AChE. Once this occurs, the enzyme is permanently inactivated, and restoration of AChE activity requires the synthesis of new enzyme molecules. Following covalent modification of AChE, the phosphorylated enzyme slowly releases one of its ethyl groups. The loss of an alkyl group, which is called aging, makes it impossible for chemical reactivators, such as pralidoxime, to break the bond between the remaining drug and the enzyme. |
| Echothiophate 2. Actions: | Actions include generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), and convulsions. Echothiophate produces intense miosis and, thus, has found therapeutic use. Intraocular pressure falls from the facilitation of outflow of aqueous humor. Atropine in high dosages can reverse many of the muscarinic and some of the central effects of echothiophate. |
| Echothiphate 3. Therapeutic uses: | An ophthalmic solution of the drug is applied topically to the eye for the chronic treatment of open-angle glaucoma. Echothiophate is not a first-line agent in the treatment of glaucoma. In addition to its other side eff ects, the potential risk for causing cataracts limits its use. |
| VII. TOXICOLOGY OF ACETYLCHOLINESTERASE INHIBITORS | AChE inhibitors are commonly used as agricultural insecticides in the United States, which has led to numerous cases of accidental intoxication with these agents. In addition, they are frequently used for suicidal and homicidal purposes. Toxicity with these agents is manifested as nicotinic and muscarinic signs and symptoms. Depending on the agent, the effects can be peripheral or affect the whole body. |
| A. Reactivation of acetylcholinesterase: | Pralidoxime can reactivate inhibited AChE. However, it is unable to penetrate into the CNS. The presence of a charged group allows it to approach an anionic site on the enzyme, where it essentially displaces the phosphate group of the organophosphate and regenerates the enzyme. If given before aging of the alkylated enzyme occurs, it can reverse the effects of echothiophate, except for those in the CNS. With the newer nerve agents, which produce aging of the enzyme complex within seconds, pralidoxime is less effective. Pralidoxime is a weak AChE inhibitor and, at higher doses, may cause side effects similar to other AChE inhibitors. In addition, it cannot overcome toxicity of reversible AChE inhibitors (for example, physostigmine). |
| Other treatments toxicity | Atropine is administered to prevent muscarinic side effects of these agents. Such effects include increased bronchial secretion and saliva, bronchoconstriction, and bradycardia. Diazepam is also administered to reduce the persistent convulsion caused by these agents. General supportive measures, such as maintenance of patent airway, oxygen supply, and artificial respiration, may be necessary as well. |
| Nicotine | Increased blood pressure and cardiac rate (due to release of transmitter from adrenergic terminals and from the adrenal medulla) and increased peristalsis and secretions. At higher doses, the blood pressure falls because of ganglionic blockade, and activity in both the GI tract and bladder musculature ceases.Generalized ganglionic stimulation: hypertension, tachycardia, nausea, vomiting, diarrhea • For smoking cessation, usually used as gum or transdermal patch Duration: 4–6 h Major overdose: convulsions, paralysis, coma |
| Varenicline | A partial agonist at N receptors Smoking cessation oral activity • Duration: ~12 h Hypertension, sweating, sensory disturbance, diarrhea, polyuria, menstrual disturbance |
| Succinylcholine | N-receptor agonist, moderately selective for neuromuscular end plate (NM receptors) Muscle relaxation Highly polar, used IV • Duration: 5–10 min Initial muscle spasms and postoperative pain • Prolonged action in persons with abnormal butyrylcholinesterase |
| Parathion | Insecticide only Duration: days to weeks Highly lipid-soluble Highly dangerous insecticide • causes all parasympathetic effects plus muscle paralysis and coma |
| Malathion | Insecticide and scabicide (topical) Duration: days Highly lipid-soluble but metabolized to inactive products in mammals and birds Much safer insecticide than parathion |
| Sarin tabun | Nerve gases • terrorist threat Like parathion but more rapid action Rapidly lethal |
| Rivastigmine, galantamine, donepezil; tacrine is obsolete | Cholinesterase inhibition plus variable other poorly understood effects Alzheimer’s disease Lipid soluble, enter CNS • Half-lives: 1.5–70 h Nausea, vomiting |
| Muscarinic Cardiovascular effects- | At therapeutic doses include an initial slowing of heart rate caused by central effects or blockade of inhibitory presynaptic muscarinic receptors on vagus nerve endings. These are followed by the tachycardia and decreased atrioventricular conduction time that would be predicted from blockade of postsynaptic muscarinic receptors in the sinus node. |
| Atropine | Atropine is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. It binds competitively and prevents acetylcholine (ACh) from binding to those sites. Atropine acts both centrally and peripherally. Its general actions last about 4 hours, except when placed topically in the eye, where the action may last for days. |
| Atropine effects | Neuroeffector organs have varying sensitivity to atropine. The greatest inhibitory effects are on bronchial tissue and the secretion of sweat and saliva. Because it is a tertiary amine, atropine is relatively lipid-soluble and readily crosses membrane barriers. The drug is well distributed into the CNS, the eye, and other organs. It is eliminated partially by metabolism in the liver and partially unchanged in the urine; half-life is approximately 2 h; and duration of action of normal doses is 4–8 h except in the eye. |
| Atropine action on eye | Atropine blocks all cholinergic activity on the eye, resulting in persistent mydriasis, unresponsiveness to light, and cycloplegia (inability to focus for near vision). In patients with narrow-angle glaucoma, intraocular pressure may rise dangerously. Shorter-acting agents, such as the antimuscarinic tropicamide, or an α -adrenergic drug, such as phenylephrine, are generally favored for producing mydriasis in ophthalmic examinations. |
| B. Gastrointestinal (GI): Atropine | Gastrointestinal (GI): Atropine (as the active isomer, l-hyoscyamine) can be used as an antispasmodic to reduce activity of the GI tract. Atropine and scopolamine are probably the most potent drugs available that produce this effect. Although gastric motility is reduced, hydrochloric acid production is not significantly affected. Thus, the drug is not effective in promoting healing of peptic ulcer. In addition, doses of atropine that reduce spasms also reduce saliva secretion, ocular accommodation, and micturition (urination). These effects decrease patient compliance with the use of these medications |
| C. Urinary system: Atropine | Urinary system: Atropine-like drugs are also used 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. |
| D. Cardiovascular: Atropine | Cardiovascular: Atropine produces divergent effects on the cardiovascular system, depending on the dose. At low doses, the predominant effect is a decreased cardiac rate (bradycardia). Originally thought to be due to central activation of vagal efferent outflow, the effect is now known to result from blockade of the M1 receptors on the inhibitory prejunctional (or presynaptic) neurons, thus permitting increased ACh release. With higher doses of atropine, the M2 receptors on the sinoatrial node are blocked, and the cardiac rate increases modestly. This generally requires at least 1 mg of atropine, which is a higher dose than ordinarily given. Arterial blood pressure is unaffected, but, at toxic levels, atropine will dilate the cutaneous vasculature. |
| E. Secretions: Atropine | Secretions: Atropine blocks the salivary glands, producing a drying effect on the oral mucous membranes (xerostomia). The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected. [Note: Inhibition of secretions by sweat glands can cause elevated body temperature, which can be dangerous in children and the elderly.] |
| Atropine theraupetic effect a. Ophthalmic: | In the eye, topical atropine exerts both mydriatic and cycloplegic effects, and it permits the measurement of refractive errors without interference by the accommodative capacity of the eye. [Note: Phenylephrine or similar α-adrenergic drugs are preferred for pupillary dilation if cycloplegia is not required]. Shorter-acting antimuscarinics (cyclopentolate and tropicamide) have largely replaced atropine due to the prolonged mydriasis observed with atropine (7–14 days versus 6–24 hours with other agents). Atropine may induce an acute attack of eye pain due to sudden increases in eye pressure in individuals with narrow-angle glaucoma. |
| B. Antispasmodic: Atropine therupetic effect | Antispasmodic: Atropine (as the active isomer, l-hyoscyamine) is used as an antispasmodic agent to relax the GI tract and bladder. |
| C. Antidote for cholinergic agonists: Atropine theraupetic effect | Antidote for cholinergic agonists: Atropine is used for the treatment of overdoses of cholinesterase inhibitor insecticides and some types of mushroom poisoning (certain mushrooms contain cholinergic substances that block cholinesterases). Massive doses of the antagonist may be required over a long period of time to counteract the poisons. The ability of atropine to enter the central nervous system (CNS) is of particular importance. The drug also blocks the effects of excess ACh resulting from acetylcholinesterase inhibitors such as physostigmine. |
| Atropine d. Antisecretory: theraupetic effect | The drug is sometimes used as an antisecretory agent to block secretions in the upper and lower respiratory tracts prior to surgery. |
| 3. Pharmacokinetics: Atropine | Pharmacokinetics: Atropine is readily absorbed, partially metabolized by the liver, and eliminated primarily in urine. It has a half-life of about 4 hours. |
| Adverse effects atropine | Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia, urinary retention, and constipation. Effects on the CNS include restlessness, confusion, hallucinations, and delirium, which may progress to depression, collapse of the circulatory and respiratory systems, and death.Atropine may be dangerous in children, because they are sensitive to its effects, particularly to the rapid increases in body temperature that it may elicit. |
| Atropine toxicity overcome | Low doses of cholinesterase inhibitors, such as physostigmine, may be used to overcome atropine toxicity. In older individuals, the use of atropine to induce mydriasis and cycloplegia is considered to be too risky, because it may exacerbate an attack of glaucoma due to an increase in intraocular pressure in someone with a latent condition. It may also induce troublesome urinary retention in this population. |
| B. Scopolamine | Scopolamine, another tertiary amine plant alkaloid, produces peripheral effects similar to those of atropine. However, scopolamine has greater action on the CNS (unlike with atropine, CNS effects are observed at therapeutic doses) and a longer duration of action in comparison to those of atropine. Pharmacokinetics and adverse effects are similar to those of atropine. |
| 1. Actions: Scopolamine | Is one of the most effective anti–motion sickness drugs available. Scopolamine also has the unusual effect of blocking short-term memory. In contrast to atropine, scopolamine produces sedation, but at higher doses it can produce excitement instead. Scopolamine may produce euphoria and is susceptible to abuse. |
| 2. Therapeutic uses: scopolamine | Although similar to atropine, therapeutic use of scopolamine is limited to prevention of motion sickness (for which it is particularly effective) and to blocking short-term memory. [Note: 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.] |
| C. Ipratropium and tiotropium | Inhaled ipratropium and inhaled tiotropium are quaternary derivatives of atropine. These agents are approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD),both chronic bronchitis and emphysema. These agents are also pending approval for treating asthma in patients who are unable to take adrenergic agonists. Because of their positive charges, these drugs do not enter the systemic circulation or the CNS, isolating their effects to the pulmonary system. Tiotropium is administered once daily, a major advantage over ipratropium, which requires dosing up to four times daily. Both are delivered via inhalation. |
| D. Tropicamide and cyclopentolate | These agents are used similarly to atropine as ophthalmic solutions for mydriasis and cycloplegia. Their duration of action is shorter than that of atropine. Tropicamide produces mydriasis for 6 hours, and cyclopentolate for 24 hours. |
| E. Benztropine and trihexyphenidyl | These agents are centrally acting antimuscarinic agents that have been used for many years in the treatment of Parkinson disease. With the advent of other drugs (for example, levodopa/carbidopa), they have been largely replaced. However, benztropine and trihexyphenidyl are useful as adjuncts with other antiparkinsonian agents to treat all types of parkinsonian syndromes, including antipsychotic-induced extrapyramidal symptoms. These drugs may be helpful in geriatric patients who cannot tolerate stimulants. |
| F. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride | These synthetic atropine-like drugs are used to treat overactive urinary bladder disease. By blocking muscarinic receptors in the bladder, intravesicular pressure is lowered, bladder capacity is increased, and the frequency of bladder contractions is reduced. |
| F. Darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium chloride side effects | Side effects of these agents include dry mouth, constipation, and blurred vision, which limit tolerability of these agents if used continually. Oxybutynin is available as a transdermal system (topical patch), which is better tolerated because it causes less dry mouth than do oral formulations, and is more widely accepted with greater patient acceptance. The overall efficacies of these antimuscarinic drugs are similar |
| IV. NEUROMUSCULAR-BLOCKING DRUGS | These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular endplate of skeletal muscle. These neuromuscular blockers are structural analogs of ACh, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the endplate of the NMJ. |
| IV. NEUROMUSCULAR-BLOCKING DRUGS uses | Neuromuscular blockers are clinically useful during surgery for producing complete muscle relaxation, without having to use higher anesthetic doses to achieve comparable muscular relaxation. Such agents are also useful in orthopedic surgery and in facilitating tracheal intubation as well. A second group of muscle relaxants, the central muscle relaxants, are used to control spastic muscle tone. These drugs include diazepam, which binds at (GABA) receptors; dantrolene, which acts directly on muscles by interfering with the release of calcium from the sarcoplasmic reticulum; and baclofen, which probably acts at GABA receptors in the CNS. |
| A. Nondepolarizing (competitive) blockers | Although tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents because of its adverse side effects. The neuromuscular-blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery. [Note: Higher doses of anesthesia may produce respiratory paralysis and cardiac depression, increasing recovery time after surgery.] Neuromuscular blockers should not be used to substitute for inadequate depth of anesthesia. |
| A. Nondepolarizing (competitive) blockers mechanism low dose | Nondepolarizing neuromuscular-blocking drugs interact with the nicotinic receptors to prevent the binding of ACh. Thus, these drugs prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with ACh at the receptor without stimulating it, they are called competitive blockers. Their action can be overcome by increasing the concentration of ACh in the synaptic gap, for example, by administration of such cholinesterase inhibitors as neostigmine, pyridostigmine, and edrophonium. Anesthesiologists often employ this strategy to shorten the duration of the neuromuscular blockade. In addition, at low doses the muscle will respond to direct electrical stimulation from a peripheral nerve stimulator to varying degrees, depending on the extent of neuromuscular blockade. |
| A. Nondepolarizing (competitive) blockers mechanism high dose | B. At high doses: Nondepolarizing blockers can block the ion channels of the endplate. This leads to further weakening of neuromuscular transmission, thereby reducing the ability of AChE inhibitors to reverse the actions of the non depolarizing muscle relaxants. With complete blockade, no direct electrical stimulation is seen. |
| 2. Actions:A. Nondepolarizing (competitive) blockers | Not all muscles are equally sensitive to blockade by competitive blockers. Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck, and trunk muscles are paralyzed. Next, the intercostal muscles are affected, and, lastly, the diaphragm muscles are paralyzed. The muscles recover in the reverse manner, with the diaphragm muscles recovering first and contracting muscles of the face and the eye recovering last. Those agents that release histamine (for example, atracurium) can produce a fall in blood pressure, flushing, and bronchoconstriction. |
| 3. Therapeutic uses:A. Nondepolarizing (competitive) blockers | These blockers are used therapeutically as adjuvant drugs in anesthesia during surgery to relax skeletal muscle. They are also used to facilitate intubation as well as during orthopedic surgery (for example, fracture alignment and dislocation corrections). |
| 4. Pharmacokinetics: Nondepolarizing (competitive) blockers | 4. Pharmacokinetics: All neuromuscular-blocking agents are injected intravenously because their uptake via oral absorption is minimal. These agents possess two or more quaternary amines in their bulky ring structure, making them orally ineffective. They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier. Many of the drugs are not metabolized, and their actions are terminated by redistribution. For example, pancuronium is excreted unchanged in urine. Atracurium is degraded spontaneously in plasma and by ester hydrolysis. [Note: Atracurium has been replaced by its isomer, cisatracurium. Atracurium releases histamine and is metabolized to laudanosine, which can provoke seizures. Cisatracurium, which has the same pharmacokinetic properties as atracurium, is less likely to have these effects.] The amino steroid drugs (vecuronium and rocuronium) are deacetylated in the liver, and their clearance may be prolonged in patients with hepatic disease. These drugs are also excreted unchanged in bile. The choice of an agent will depend on how quickly muscle relaxation is needed and on the duration of the muscle relaxation. The onset and duration of action, as well as other characteristics of the neuromuscular blocking drugs |
| B. Halogenated hydrocarbon anesthetics: | Drugs such as halothane act to enhance neuromuscular blockade by exerting a stabilizing action at the NMJ. These agents sensitize the NMJ to the effects of neuromuscular blockers. |
| C. Aminoglycoside antibiotics: | Drugs such as gentamicin and tobramycin inhibit ACh release from cholinergic nerves by competing with calcium ions. They synergize with pancuronium and other competitive blockers, enhancing the blockade. |
| D. Calcium-channel blockers: | These agents may increase the neuromuscular block of competitive blockers as well as depolarizing blockers. |
| B. Depolarizing agents | Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to the action of ACh. However, these agents are more resistant to degradation by AChE, and can thus more persistently depolarize the muscle fibers. Succinylcholine is the only depolarizing muscle relaxant in use today. |
| 1. Mechanism of action: depolarizing agents | The depolarizing neuromuscular-blocking drug succinylcholine attaches to the nicotinic receptor and acts like ACh to depolarize the junction. Unlike ACh, which is instantly destroyed by AChE, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing constant stimulation of the receptor. [Note: The duration of action of succinylcholine is dependent on diffusion from the motor endplate and hydrolysis by plasma pseudocholinesterase.] The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor (Phase I). This leads to a transient twitching of the muscle (fasciculations). Continued binding of the depolarizing agent renders the receptor incapable of transmitting further impulses. With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked. This causes a resistance to depolarization (Phase II) and flaccid paralysis. |
| 2. Actions: depolarizing agents | The sequence of paralysis may be slightly different, but, as with the competitive blockers, the respiratory muscles are paralyzed last. Succinylcholine initially produces brief muscle fasciculations and a ganglionic block except at high doses, but it does have weak histamine-releasing action. [Note: Administering a small dose of nondepolarizing neuromuscular blocker prior to succinylcholine helps decrease or prevent the fasciculations which cause muscle soreness.] Normally, the duration of action of succinylcholine is extremely short, because this drug is rapidly broken down by plasma pseudocholinesterase. However, succinylcholine that gets to the NMJ is not metabolized by AChE, allowing the agent to bind to nicotinic receptors, and redistribution to plasma is necessary for metabolism (therapeutic benefits last only for a few minutes). [Note: Genetic variants in which plasma pseudocholinesterase levels are low or absent leads to prolonged neuromuscular paralysis.] |
| 3. Therapeutic uses: depolarizing agents | 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 used during electroconvulsive shock treatment. |
| 4. Pharmacokinetics: depolarizing agents | Succinylcholine is injected intravenously. Its brief duration of action (several minutes) results from redistribution and rapid hydrolysis by plasma pseudocholinesterase. Therefore, it is sometimes given by continuous infusion to maintain a longer duration of effect. Drug effects rapidly disappear upon discontinuation. |
| A. Hyperthermia depolarizing agents | When halothane is used as an anesthetic, administration of succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity, metabolic acidosis, tachycardia, and hyperpyrexia) in genetically susceptible people. This is treated by rapidly cooling the patient and by administration of dantrolene, which blocks release of Ca2+ from the sarcoplasmic reticulum of muscle cells, thereby reducing heat production and relaxing muscle tone. |
| B. Apnea: depolarizing agents | Administration of succinylcholine to a patient who is genetically deficient in plasma cholinesterase or who has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm. The rapid release of potassium may also contribute to prolonging apnea in patients with electrolyte imbalances who receive this drug. Patients with electrolyte imbalances who are also receiving digoxin or diuretics (such as congestive heart failure patients) should use succinylcholine cautiously or not at all. |
| C. Hyperkalemia: depolarizing agents | Succinylcholine increases potassium release from intracellular stores. This may be particularly dangerous in burn patients and patients with massive tissue damage in which potassium has been rapidly lost from within cells. |
| 1. CNS— uses muscarinic agents | 1. CNS—Scopolamine is standard therapy for motion sickness; it is one of the most effective agents available for this condition. A transdermal patch formulation is available. Benztropine, biperiden, and trihexyphenidyl are representative of several antimuscarinic agents used in parkinsonism. Although not as effective as levodopa, these agents may be useful as adjuncts or when patients become unresponsive to levodopa. Benztropine is sometimes used parenterally to treat acute dystonias caused by first generation antipsychotic medications. |
| Eye uses antimuscarinic agents | Antimuscarinic drugs are used to cause mydriasis, as indicated by the origin of the name belladonna (“beautiful lady”) from the ancient cosmetic use of extracts of the Atropa belladonna plant to dilate the pupils. They also cause cycloplegia and prevent accommodation. In descending order of duration of action, these drugs are atropine (>72 h), homatropine (24 h), cyclopentolate (2–12 h), and tropicamide (0.5–4 h). These agents are all well absorbed from the conjunctival sac into the eye. |
| 3. Bronchi— uses antimuscarinic agents | Parenteral atropine has long been used to reduce airway secretions during general anesthesia. Ipratropium is a quaternary antimuscarinic agent used by inhalation to promote bronchodilation in asthma and chronic obstructive pulmonary disease (COPD). Although not as efficacious as β agonists, ipratropium is less likely to cause tachycardia and cardiac arrhythmias in sensitive patients. It has very few antimuscarinic effects outside the lungs because it is poorly absorbed and rapidly metabolized. Tiotropium is an analog with a longer duration of action. Aclidinium is a newer long-acting antimuscarinic drug available in combination with a long-acting β2-adrenoceptor agonist for the treatment of COPD. |
| 4. Gut— antimuscarinic agents | Atropine, methscopolamine, and propantheline were used in the past to reduce acid secretion in acid-peptic disease, but are now obsolete for this indication because they are not as effective as H2 blockers and proton pump inhibitors, and they cause far more frequent and severe adverse effects. The M1-selective inhibitor pirenzepine is available in Europe for the treatment of peptic ulcer. Muscarinic blockers can also be used to reduce cramping and hypermotility in transient diarrheas, but drugs such as diphenoxylate and loperamide are more effective. |
| 5. Bladder— antimuscarinic agents | Oxybutynin, tolterodine, or similar agents may be used to reduce urgency in mild cystitis and to reduce bladder spasms after urologic surgery. Tolterodine, darifenacin, solifenacin, fesoterodine, and propiverine are slightly selective for M3 receptors and are promoted for the treatment of stress incontinence. |
| 6. Cholinesterase inhibitor intoxication— antimuscarinic agents | Atropine, given parenterally in large doses, reduces the muscarinic signs of poisoning with AChE inhibitors. Pralidoxime is used to regenerate active AChE. |
| General muscarinic agents toxicity | Blockade of thermoregulatory sweating may result in hyperthermia or atropine fever. This is the most dangerous effect of the antimuscarinic drugs in children and is potentially lethal in infants. Sweating, salivation, and lacrimation are all significantly reduced or stopped. Moderate tachycardia is common, and severe tachycardia or arrhythmias are common with large overdoses. In the elderly, important toxicities include acute angle-closure glaucoma and urinary retention, especially in men with prostatic hyperplasia. Constipation and blurred vision are common adverse effects in all age groups. CNS toxicity includes sedation, amnesia, and delirium or hallucinations; convulsions may also occur. Central muscarinic receptors are probably involved. Other drug groups with antimuscarinic effects, for example, tricyclic antidepressants, may cause hallucinations or delirium in the elderly, who are especially susceptible to antimuscarinic toxicity. At very high doses, intraventricular conduction may be blocked; this action is probably not mediated by muscarinic blockade and is difficult to treat. Dilation of the cutaneous vessels of the arms, head, neck, and trunk also occurs at these doses; the resulting “atropine flush” may be diagnostic of overdose with these drugs. |
| 3. Treatment of toxicity— muscarinic agents | 3. Treatment of toxicity—Treatment of toxicity is usually symptomatic. Severe tachycardia may require cautious administration of small doses of physostigmine. Hyperthermia can usually be managed with cooling blankets or evaporative cooling. |
| F. Contraindications | Danger of hyperthermia glaucoma, especially the closed angle form, and in men with prostatic hyperplasia. |
| A. Ganglion-Blocking Drugs | Blockers of ganglionic nicotinic receptors act like competitive pharmacologic antagonists, although there is evidence that some also block the pore of the nicotinic channel itself. These drugs were the first successful agents for the treatment of hypertension. Hexamethonium (C6, a prototype), mecamylamine, and several other ganglion blockers were extensively used for this disease. Unfortunately, the adverse effects of ganglion blockade in hypertension are so severe (both sympathetic and parasympathetic divisions are blocked) that patients were unable to tolerate them for long periods. |
| Trimethaphan | Trimethaphan was the ganglion blocker most recently used in clinical practice, but it too has been almost abandoned. It is poorly lipid-soluble, inactive orally, and has a short half-life. It was used intravenously to treat severe accelerated hypertension (malignant hypertension) and to produce controlled hypotension. These drugs are still used in research. |
| Ganglion blockers adverse effects | Because ganglion blockers interrupt sympathetic control of venous tone, they cause marked venous pooling; postural hypotension is a major manifestation of this effect. Other toxicities of ganglion-blocking drugs include dry mouth, blurred vision, constipation, and severe sexual dysfunction. As a result,ganglion blockers use |
| CHOLINESTERASE REGENERATORS | Pralidoxime is the prototype cholinesterase regenerator. These chemical antagonists contain an oxime group, which has an extremely high affinity for the phosphorus atom in organophosphate insecticides. Because the affinity of the oxime group for phosphorus exceeds the affinity of the enzyme-active site for phosphorus, these agents are able to bind the inhibitor and displace the enzyme if aging has not occurred. The active enzyme is thus regenerated. Pralidoxime, is used to treat patients exposed to high doses of organophosphate AChE inhibitor insecticides, such as parathion, or to nerve gases. It is not recommended for use in carbamate AChE inhibitor overdosage. |