Parasympathomimetics and Parasympatholytics PDF

PARASYMPATHOMIMETICS Dr Sarah Fazalul 2023 | sarahfazalul  What we want to achieve at the end of this topic? To understand the various classes of cholinergic agonists, their mechanism of actions, side effects an...

PARASYMPATHOMIMETICS Dr Sarah Fazalul 2023 | sarahfazalul  What we want to achieve at the end of this topic? To understand the various classes of cholinergic agonists, their mechanism of actions, side effects and contraindications of parasympathomimetic agents 2023 | sarahfazalul  DRUGS AFFECTING PERIPHERAL NERVOUS SYSTEM Local Anaesthetic Agent Neuromuscular Blocker Sympathomimetic Sympatholytic Parasympathomimetic Parasympatholytic Ganglion Blocker 2023 | sarahfazalul  All autonomic ganglia have nicotinic receptors All target organs of the parasympathetic nervous system have muscarinic receptors All receptors at the neuromuscular junction are nicotinic receptors *There are cholinergic receptors such as in the CNS and sweat glands innervated by the sympathetic nervous system Physiological responses upon activation of parasympathetic system 2023 | sarahfazalul  Nicotinic type 1 Nicotinic type 2 Nn Nm Neuronal nicotinic receptors Muscle nicotinic receptors 2023 | sarahfazalul  Only N2 is relevant here Effector organs: Cardiac and smooth muscles, gland cells and nerve terminals Physiological responses upon activation of parasympathetic system 2023 | sarahfazalul Molecular Mechanisms of Action 1. Gq protein coupling of M1 and M3 muscarinic receptors to phospholipase C, releasing DAG and IP3. Both DAG and IP3 are important in secretion and release of intracellular calcium, respectively 2. M2 muscarinic receptors couple to adenylate cyclase through the inhibitory Gi-coupling protein. 3. Coupling of M2 receptors to potassium channels in the heart and elsewhere, facilitate opening of these channels M4 and M5 receptors have no major roles in periphery. Important in the CNS  Site of action of cholinergic receptors and the respective physiological responses 2023 | sarahfazalul  Parasympathomimetics Drugs that mimic the action of ACh and increase the activity in cholinergic neurons through binding at the muscarinic receptors Produce similar responses as during parasympathetic system activation Also known as cholinomimetics, cholinergic drugs, muscarinic receptor agonists 2023 | sarahfazalul  Classification of parasympathomimetics the postsynaptic inhibition of muscarinic receptor cholinesterase the prototype the prototype 2023 | sarahfazalul 2023 | sarahfazalul  Direct-acting sympathomimetics Choline esters Alkaloids Acetylcholine Muscarine Methacholine Pilocarpine Bethanechol Not metabolised by cholinesterase Carbachol due to their complex structure 2023 | sarahfazalul  Clinical uses of choline esters Bethanechol Carbachol Pilocarpine Selectively acts on urinary As miotic agent applied after A miotic agent used to treat bladder and GIT. Increasing the cataract surgery. Causes miosis glaucoma and ocular tone of detrusor muscle and and increase amount of fluid hypertension by allowing smooth muscle (GIT), hence that drain from the eyes, excess fluid to drain from the promoting bladder emptying thereby reducing intraocular eye. Treat presbyopia by (urination) and GI peristalsis. pressure. reducing the size of the pupils Clinically used in which helps to see objects up postoperative/postpartum close. Also useful for treatment urinary retention, neurogenic of Sjögren's syndrome and bladder and paralytic ileus the relief of radiation-induced xerostomia' symptoms. 2023 | sarahfazalul  Indirect-acting drugs: Inhibition of acetylcholinesterase The enzyme breaks down the ACh into acetic acid and choline so that it does not over-stimulate post-synaptic nerves, muscles and exocrine glands The indirect-acting cholinomimetics hydrolyse acetylcholinesterase, causing accumulation of ACh and enhances stimulation of postsynaptic cholinergic receptors 2023 | sarahfazalul  Cholinesterase inhibitors Reversible inhibitors (including Irreversible inhibitors carbamates) (Organophosphates) Edrophonium, neostigmine, Isoflurophate, parathion, sarin, malathion pyridostigmine, physostigmine Water-soluble Lipid-soluble (cross BBB and skin) Medically therapeutic Mainly as insecticides and nerve gas Common effects: tremor, anxiety, restlessness to coma (CNS related) Compete with ACh for active site on the cholinesterase enzyme Can affect nicotinic receptors (at NMJ) 2023 | sarahfazalul  Clinical uses of cholinesterase inhibitors Therapeutically for treating glaucoma, myasthenia gravis, reversing atropine poisoning, reversing curare and NMJ blockers Adverse effects of parasympathomimetics Blurred vision Excessive sweating Significant salivation Increased GI mortality – nausea, diarrhea Bradycardia Urinary urgency Organophosphates poisoning What is it? Assist respiration Atropine in adequate doses Cholinesterase reactivator (e.g.pralidoxime) Find out how..  PARASYMPATHOLYTICS Dr Sarah Fazalul 2023 | sarahfazalul  What we want to achieve at the end of this topic? To understand the various classes of parasympatholytics, their mechanisms of action and side effects 2023 | sarahfazalul  DRUGS AFFECTING PERIPHERAL NERVOUS SYSTEM Local Anaesthetic Agent Neuromuscular Blocker Sympathomimetic Sympatholytic Parasympathomimetic Parasympatholytic Ganglion Blocker 2023 | sarahfazalul  Parasympatholytics Drugs that block or lyse the effects of acetylcholine via competitive antagonism at the muscarinic cholinergic receptor Also known as cholinergic antagonists, anticholinergics, antimuscarinics Produce vary responses in the effectors organs (depend on their sensitivity to the to the blocking effects of antagonists) Sensitivity Secretions of bronchial, salivary and sweat glands Dilation of the pupils and tachycardia due to blockade of vagal tone in the heart Inhibit parasympathetic control of GIT and bladder Dose 2023 | sarahfazalul  Their blocking effects can be overcome by increased concentrations of muscarinic agonists Common responses Dry eyes Dry mouth Blurred vision Constipation Urinary retention M1, M2 and M3 Pharmacodynamics of anticholinergic drugs and associated physiological responses 2023 | sarahfazalul  Effects of muscarinic blocking drugs acting at respective muscarinic receptors 2023 | sarahfazalul  Classification of parasympatholytics Not receptor blockers but rather are antagonists of organophosphates 2023 | sarahfazalul  Belladona alkaloids ATROPINE SCOPOLAMINE IPRATROPIUM trihexylphenidyl Benztropine Dicyclomine glycopyrrolate Cyclopentolate Synthetic antimuscarinics tropicamide Propantheline Oxybutynin pirenzepine 2023 | sarahfazalul  ATROPINE SCOPOLAMINE Blocks M1, M2 and M3 receptors on the effector organs Also known as deadly nightshade 2023 | sarahfazalul  Effects: Increase HR, decrease secretions (saliva, sweat, bronchial, lachrymal, nasal, gastric and intestinal), decrease intestinal motility and micturition (urination), pupil dilation (mydriatic), risk of increased intraocular pressure, photophobia, colic, emotional lability with head injuries, antidote for cholinergic drugs Lipid soluble and readily crosses BBB. Well distributed in the CNS, the eye and other organs. Eliminated partially by metabolism in the liver and partially unchanged in the urine. Half-life is around 2 h, duration of action is usually 4-8 h (except in the eye) No CNS effect at therapeutic dose (except among elderly – confusion). At toxic doses, CNS adverse ATROPINE effects are prominent – hallucination, delirium, irritability, Therapeutic dose: 0.5-1.0 mg circulatory collapse, respiratory failure, paralysis and coma 2023 | sarahfazalul  Dose-related effects of atropine in adult Dose Effects 0.5 – 1 mg Dry mouth, dry skin 2 mg Dilated pupils, tachycardia 5 mg Very dry mouth and skin Reduced GIT and bladder tone Reduced gastric secretion CNS effects 10 mg CNS toxicity 100 – 200 mg Coma 2023 | sarahfazalul  Atropine poisoning 2023 | sarahfazalul  Atropine substitutes The drugs are related to atropine but differ in terms of their specific activities The quaternary compounds are fully ionised in the pH range of body fluids, hence have reduced lipid solubility Examples: homatropine, dicyclomine, propantheline, ipratropium, tolterodine 2023 | sarahfazalul  IPRATOPIUM TOLTERODINE Potent action on reducing secretions in the lungs Commonly used as anticholinergic bronchodilator in asthmatic patients For treatment of urinary frequency and who do not tolerate adrenergic agonist; urgency cause by bladder overactivity. also useful for managing COPD (Other drugs used for this condition: oxybutynin, propantheline, hyoscyamine and Does not enter CNS & tricyclic antidepressant) systemic circulation Shows a much lower incidence of dry Available as mouth due to its specificity for the liquid aerosol for bladder as opposed to salivary glands inhalation (vs solifenacin which causes dry mouth) Not to be used in patients with narrow- angle glaucoma – WHY? 2023 | sarahfazalul  Usually in adults for the prevention of nausea and vomiting associated with motion sickness and for the prevention of postoperative nausea and vomiting (PONV) associated with anaesthesia or opiate analgesia Greater permeation of scopolamine across the BBB as compared to the atropine, cause greater CNS effects – drowsiness, fatigue and dreamless sleep Has unusual effect of blocking short-term memory (amnesia). At higher dose, may cause excitement. At toxic doses, CNS adverse effects are prominent – hallucination, delirium, irritability, circulatory collapse, respiratory failure, paralysis and coma SCOPOLAMINE 2023 | sarahfazalul  Clinical indications of parasympatholytics Antisecretory agent IV atropine is usually given before anesthesia to reduce excessive salivary and airway secretion caused by some inhalation of during anaesthesia anesthetics and suxamethonium. Ophthalmic Topical atropine, cyclopentolate and tropicamide exert both mydriatic and cycloplegic effects, which are useful in eye examination examination. Atropine is used as antispasmodic agent to relax the GIT and Antispasmodic agent bladder. Scoplamine is primarily used to prevent nausea and vomiting Antidote for cholinergic Treatment of overdosed cholinesterase inhibitors (organophosphates); Mushroom poisoning (contain cholinergic agonist toxicity substance that block cholinesterase) 2023 | sarahfazalul  Other clinical indications of parasympatholytics Treat parkinsonism (by blocking the stimulating effects of ACh) - trihexyphenidyl Relieve bradycardia caused by a hyperactive carotid sinus reflex - atropine Relieve pylorospasm and hyperactive bowel - pirenzepine Inhibit involuntary bladder contraction - propantheline Treatment of irritable bowel syndrome - propantheline, dicyclomine Treat overactive bladder - solifenacin, tolterodine Control rhinorrhea associated with hay fever - ipratopium Block the effects of ACh in CNS (in treating motion sickness and preventing nausea vomiting) - scopolamine 2023 | sarahfazalul  Effects if parasympathetic stimulation and blockade Stimulation Blockade 2023 | sarahfazalul  7 C H A P T E R Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs Drugs with acetylcholine-like effects (cholinomimetics) con- their spectrum of action (ie, whether they act on muscarinic or sist of 2 major subgroups on the basis of their mode of action nicotinic cholinoceptors). (ie, whether they act directly at the acetylcholine receptor or Acetylcholine may be considered the prototype that acts indirectly through inhibition of cholinesterase). Drugs in the directly at both muscarinic and nicotinic receptors. Neostigmine direct-acting subgroup are further subdivided on the basis of is a prototype for the indirect-acting cholinesterase inhibitors. Cholinomimetic (cholinergic) drugs Direct-acting Indirect-acting Organophosphates Muscarinic Nicotinic (very long acting) (parathion) Carbamates (intermediate to long acting) (neostigmine) Choline esters Alkaloids Edrophonium (short acting) (acetylcholine) (pilocarpine) DIRECT-ACTING CHOLINOMIMETIC A. Classification AGONISTS Muscarinic agonists are parasympathomimetic; that is, they mimic the actions of parasympathetic nerve stimulation in addition to other This class comprises a group of choline esters (acetylcholine, metha- effects. Five subgroups of muscarinic receptors have been identified choline, carbachol, bethanechol) and a second group of naturally (Table 7–2), but the muscarinic agonists available for clinical use acti- occurring alkaloids (muscarine, pilocarpine, nicotine, lobeline). vate them nonselectively. Nicotinic agonists act on both ganglionic Newer drugs are occasionally introduced for special applications. or neuromuscular cholinoceptors; agonist selectivity is limited. On The members differ in their spectrum of action (amount of mus- the other hand, a few slightly selective muscarinic antagonists and a carinic versus nicotinic stimulation) and in their pharmacokinetics separate group of relatively selective nicotinic receptor antagonists are (Table 7–1). Both factors influence their clinical use. available (Chapter 8). 60  CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 61 High-Yield Terms to Learn Choline esters A cholinomimetic drug consisting of choline (an alcohol) or a choline derivative, esterified with an acidic substance (eg, acetic or carbamic acid); usually poorly lipid-soluble Cholinergic crisis The clinical condition of excessive activation of cholinoceptors; it may include skeletal muscle weak- ness as well as parasympathetic effects, usually caused by cholinesterase inhibitors; cf myasthenic crisis Cholinomimetic alkaloids A drug with weakly alkaline properties (usually an amine of plant origin) whose effects resemble those of acetylcholine; usually lipid-soluble Cyclospasm Marked contraction of the ciliary muscle; maximum accommodation for close vision Direct-acting A drug that binds and activates cholinoceptors; the effects mimic those of acetylcholine cholinomimetic Endothelium-derived A potent vasodilator substance, largely nitric oxide (NO), that is released from vascular endothelial relaxing factor (EDRF) cells Indirect-acting A drug that amplifies the effects of endogenous acetylcholine by inhibiting acetylcholinesterase cholinomimetic Muscarinic agonist A cholinomimetic drug that binds muscarinic receptors and has primarily muscarine-like actions Myasthenic crisis In patients with myasthenia, an acute worsening of symptoms; usually relieved by increasing cholin- esterase inhibitor treatment; cf cholinergic crisis Nicotinic agonist A cholinomimetic drug that binds nicotinic receptors and has primarily nicotine-like actions Organophosphate An ester of phosphoric acid and an alcohol that inhibits cholinesterase Organophosphate aging A process whereby the organophosphate, after binding to cholinesterase, is chemically modified and becomes more firmly bound to the enzyme Parasympathomimetic A drug whose effects resemble those of stimulating the parasympathetic nerves TABLE 7–1 Some cholinomimetics: spectrum of action and pharmacokinetics. Drug Spectrum of Actiona Pharmacokinetic Features Direct-acting Acetylcholine B Rapidly hydrolyzed by cholinesterase (ChE); duration of action 5–30 s; poor lipid solubility Bethanechol M Resistant to ChE; orally active, poor lipid solubility; duration of action 30 min to 2 h Carbachol B Like bethanechol Pilocarpine M Not an ester, good lipid solubility; duration of action 30 min to 2 h Nicotine N Not an ester; duration of action 1–6 h; high lipid solubility Varenicline N Partial agonist at N receptors, high lipid solubility; duration 12–24 h Indirect-acting Edrophonium B Alcohol, quaternary amine, poor lipid solubility, not orally active; duration of action 5–15 min Neostigmine B Carbamate, quaternary amine, poor lipid solubility, orally active; duration of action 30 min to 2 h or more Physostigmine B Carbamate, tertiary amine, good lipid solubility, orally active; duration of action 30 min to 2 h Pyridostigmine B Carbamate, like neostigmine, but longer duration of action (4–8 h) Echothiophate B Organophosphate, moderate lipid solubility; duration of action 2–7 days Parathion B Organophosphate, high lipid solubility; duration of action 7–30 days; insecticide Sarin B Organophosphate, very high lipid solubility, nerve gas a B, both M and N; M, muscarinic; N, nicotinic. 62 PART II Autonomic Drugs TABLE 7–2 Cholinoceptor types and their C. Tissue and Organ Effects postreceptor mechanisms. The tissue and organ system effects of cholinomimetics are sum- marized in Table 7–3. Note that vasodilation is not a parasym- Receptor Type G Protein Postreceptor Mechanisms pathomimetic response (ie, it is not evoked by parasympathetic M1 Gq ↑ IP3, DAG cascade nerve discharge, even though directly acting cholinomimetics cause vasodilation). This vasodilation results from the release of endothe- M2 Gi ↓ cAMP synthesis lium-derived relaxing factor (EDRF; nitric oxide and possibly other M3 Gq ↑ IP3, DAG cascade substances) in the vessels, mediated by uninnervated muscarinic receptors on the endothelial cells. Note also that decreased blood M4 Gi ↓ cAMP synthesis pressure evokes the baroreceptor reflex, resulting in strong com- M5 Gq ↑ IP3, DAG cascade pensatory sympathetic discharge to the heart. As a result, injections of small to moderate amounts of direct-acting muscarinic cholino- NM None Na+/K+ depolarizing current mimetics often cause tachycardia, whereas parasympathetic (vagal) NN None Na+/K+ depolarizing current nerve discharge to the heart causes bradycardia. Another effect seen with cholinomimetic drugs but not with parasympathetic nerve cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol- 1,4,5-trisphosphate. stimulation is thermoregulatory (eccrine) sweating; this is a sympa- thetic cholinergic effect (see Chapter 6). The tissue and organ level effects of nicotinic ganglionic stimulation depend on the autonomic innervation of the organ involved. The blood vessels are dominated by sympathetic inner- SKILL KEEPER: DRUG METABOLISM vation; therefore, nicotinic receptor activation results in vasocon- (SEE CHAPTER 4) striction mediated by sympathetic postganglionic nerve discharge. The gut is dominated by parasympathetic control; nicotinic drugs Acetylcholine is metabolized in the body by hydrolysis of the increase motility and secretion because of increased parasympa- ester bond. Is this a phase I or phase II metabolic reaction? The Skill Keeper Answer appears at the end of the chapter. thetic postganglionic neuron discharge. Nicotinic neuromuscular end plate activation by direct-acting drugs results in fasciculations and spasm of the muscles involved. Prolonged activation results in B. Molecular Mechanisms of Action paralysis (see Chapter 27), which is an important hazard of expo- 1. Muscarinic mechanisms—Muscarinic receptors are G protein- sure to nicotine-containing and organophosphate insecticides. coupled receptors (GPCRs) (Table 7–2). Gq protein coupling of M1 and M3 muscarinic receptors to phospholipase C, a D. Clinical Use membrane-bound enzyme, leads to the release of the second mes- Several clinical conditions benefit from an increase in cholinergic sengers, diacylglycerol (DAG) and inositol-1,4,5-trisphosphate activity, including glaucoma, Sjogren’s syndrome, and loss of normal (IP3). DAG modulates the action of protein kinase C, an enzyme PANS activity in the bowel and bladder. Direct-acting nicotinic important in secretion, whereas IP3 evokes the release of calcium agonists are used in smoking cessation and to produce skeletal muscle from intracellular storage sites, which in smooth muscle results in paralysis (succinylcholine, Chapter 27). Indirect-acting agents are contraction. M2 muscarinic receptors couple to adenylyl cyclase used when increased nicotinic activation is needed at the neuromus- through the inhibitory Gi-coupling protein. A third mechanism cular junction (see discussion of myasthenia gravis). Nicotine and couples the same M2 receptors via the βγ subunit of the G protein related neonicotinoids are used as insecticides despite reported toxic to potassium channels in the heart and elsewhere; muscarinic effects on bee colonies. Varenicline is a newer nicotinic agonist with agonists facilitate opening of these channels. M4 and M5 receptors partial agonist properties. It appears to reduce craving in persons may be important in the central nervous system (CNS) but have addicted to nicotine through a nonautonomic action. not been shown to play major roles in peripheral organs. E. Toxicity 2. Nicotinic mechanism—The mechanism of nicotinic action The signs and symptoms of overdosage are readily predicted from has been clearly defined. The nicotinic acetylcholine receptor the general pharmacology of acetylcholine. is located on a channel protein that is selective for sodium and potassium. When the receptor is activated, the channel opens 1. Muscarinic toxicity—These effects include CNS stimulation and depolarization of the cell occurs as a direct result of the (uncommon with choline esters and pilocarpine), miosis, spasm influx of sodium, causing an excitatory postsynaptic potential of accommodation, bronchoconstriction, excessive gastrointestinal (EPSP). If large enough, the EPSP evokes a propagated action and genitourinary smooth muscle activity, increased secretory activ- potential in the surrounding membrane. The nicotinic receptors ity (sweat glands, airway, gastrointestinal tract, lacrimal glands), on sympathetic and parasympathetic ganglion neurons (NN, also and vasodilation. Transient bradycardia occurs, followed by reflex denoted NG) differ slightly from those on neuromuscular end tachycardia if the drug is administered as an intravenous bolus; plates (NM). reflex tachycardia occurs otherwise. Muscarine and similar alkaloids  CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 63 TABLE 7–3 Effects of cholinomimetics on major organ systems. Organ Responsea CNS Complex stimulatory effects. Nicotine: elevation of mood, alerting, addiction (nicotine-naïve individuals often suffer nausea and vomiting on initial exposure); physostigmine: convulsions; excessive concentra- tions may cause coma Eye Sphincter muscle of iris Contraction (miosis) Ciliary muscle Contraction (accommodation for near vision), cyclospasm Heart Sinoatrial node Decrease in rate (negative chronotropy), but note important reflex response in intact subject (see text) Atria Decrease in contractile force (negative inotropy); decrease in refractory period Atrioventricular node Decrease in conduction velocity (negative dromotropy), increase in refractory period Ventricles Small decrease in contractile force Blood vessels Dilation via release of EDRF from endothelium Bronchi Contraction (bronchoconstriction) Gastrointestinal tract Motility Increase in smooth muscle contraction, peristalsis Sphincters Decrease in tone, relaxation (Exception: gastroesophageal sphincter contracts) Urinary bladder Detrusor Increase in contraction Trigone and sphincter Relaxation; voiding Skeletal muscle Activation of neuromuscular end plates, contraction Glands (exocrine) Increased secretion (thermoregulatory sweating, lacrimation, salivation, bronchial secretion, gastrointesti- nal glands) a Only the direct effects are indicated; homeostatic responses to these direct actions may be important (see text). EDRF, endothelium-derived relaxing factor (primarily nitric oxide). are found in certain mushrooms (Inocybe species and Amanita mus- (carbamates) and phosphoric acid esters (organophosphates). caria) and are responsible for the short-duration type of mushroom These drugs are acetylcholinesterase (AChE) inhibitors. Neo- poisoning, which is characterized by nausea, vomiting, and diar- stigmine is a prototypic carbamate, whereas parathion, an impor- rhea. (The much more dangerous and potentially lethal form of tant insecticide, is a prototypic organophosphate. A third class has mushroom poisoning from Amanita phalloides and related species only one clinically useful member: edrophonium is an alcohol involves initial vomiting and diarrhea but is followed by hepatic (not an ester) with a very short duration of action. and renal necrosis. It is not caused by muscarinic agonists but by amanitin and phalloidin, RNA polymerase inhibitors.) B. Mechanism of Action Both carbamate and organophosphate inhibitors bind to cholin- 2. Nicotinic toxicity—Toxic effects include ganglionic stimula- esterase and undergo prompt hydrolysis. The alcohol portion of tion and block and neuromuscular end plate depolarization leading the molecule is then released. The acidic portion (carbamate ion to fasciculations and then paralysis. The neuromuscular effects are or phosphate ion) is released much more slowly from the enzyme described in greater detail in Chapter 27. CNS toxicity includes active site, preventing the binding and hydrolysis of endogenous stimulation (including convulsions) followed by depression. Nico- acetylcholine. As a result, these drugs amplify acetylcholine effects tine in small doses, ie, via smoking, is strongly addicting. wherever the transmitter is released. Edrophonium, though not an ester, has sufficient affinity for the enzyme active site to similarly prevent access of acetylcholine for 5–15 min. After hydrolysis, INDIRECT-ACTING AGONISTS carbamates are released by cholinesterase over a period of 2–8 h. Organophosphates are long-acting drugs; they form an extremely A. Classification and Prototypes stable phosphate complex with the enzyme. After initial hydroly- Hundreds of indirect-acting cholinomimetic drugs have been sis, the phosphoric acid residue is released over periods of days to synthesized in 2 major chemical classes: carbamic acid esters weeks. Recovery is due in part to synthesis of new enzyme. 64 PART II Autonomic Drugs C. Effects Because of their toxicity and short persistence in the environ- By inhibiting cholinesterase, these agents cause an increase in the ment, organophosphates are used extensively in agriculture as concentration, half-life, and actions of acetylcholine in synapses insecticides and antihelminthic agents; examples are malathion where acetylcholine is released physiologically. Therefore, the and parathion. Some of these agents (eg, malathion, dichlorvos) indirect agents have muscarinic or nicotinic effects depending on are relatively safe in humans because they are metabolized rapidly which organ system is under consideration. Cholinesterase inhibi- to inactive products in mammals (and birds) but not in insects. tors do not have significant actions at uninnervated sites where Some are prodrugs (eg, malathion, parathion) and must be metab- acetylcholine is not normally released (eg, vascular endothelial olized to the active product (malaoxon from malathion, paraoxon cells). from parathion). The signs and symptoms of poisoning are the same as those described for the direct-acting agents, with the fol- D. Clinical Uses lowing exceptions: vasodilation is a late and uncommon effect; The clinical applications of the AChE inhibitors are predictable bradycardia is more common than tachycardia; CNS stimulation from a consideration of the organs and the diseases that benefit is common with organophosphate and physostigmine overdosage from an amplification of cholinergic activity. These applications and includes convulsions, followed by respiratory and cardiovas- are summarized in the Drug Summary Table. Carbamates, cular depression. The spectrum of toxicity can be remembered which include neostigmine, physostigmine, pyridostigmine, with the aid of the mnemonic DUMBBELSS (diarrhea, urination, and ambenonium, are used far more often in therapeutics than miosis, bronchoconstriction, bradycardia, excitation [of skeletal are organophosphates. The treatment of myasthenia is especially muscle and CNS], lacrimation, and salivation and sweating). important. (Because myasthenia is an autoimmune disorder, treatment may also include thymectomy and immunosuppressant drugs.) Rivastigmine, a carbamate, and several other cholinester- ase inhibitors are used exclusively in Alzheimer’s disease. A por- 1. A 30-year-old woman undergoes abdominal surgery. In spite tion of their action may be due to other, unknown mechanisms. of minimal tissue damage, complete ileus (absence of bowel Although their effects are modest and temporary, these drugs are motility) follows, and she complains of severe bloating. She frequently used in this devastating condition. Some carbamates also finds it difficult to urinate. Mild cholinomimetic stimu- (eg, carbaryl) are used in agriculture as insecticides. Two organo- lation with bethanechol or neostigmine is often effective in phosphates used in medicine are malathion (a scabicide) and relieving these complications of surgery. Neostigmine and bethanechol in moderate doses have significantly different metrifonate (an antihelminthic agent). effects on which one of the following? Edrophonium is used for the rapid reversal of nondepolarizing (A) Gastric secretory cells neuromuscular blockade (Chapter 27), in the diagnosis of myas- (B) Vascular endothelium thenia, and in differentiating myasthenic crisis from cholinergic (C) Salivary glands crisis in patients with this disease. Because cholinergic crisis can (D) Sweat glands result in muscle weakness like that of myasthenic crisis, distin- (E) Ureteral tone guishing the 2 conditions may be difficult. Administration of a 2. Parathion has which one of the following characteristics? short-acting cholinomimetic, such as edrophonium, will improve (A) It is inactivated by conversion to paraoxon muscle strength in myasthenic crisis but weaken it in cholinergic (B) It is less toxic to humans than malathion crisis. (C) It is more persistent in the environment than DDT (D) It is poorly absorbed through skin and lungs E. Toxicity (E) If treated early, its toxicity may be partly reversed by pralidoxime In addition to their therapeutic uses, some AChE inhibitors (especially organophosphates) have clinical importance because 3. Ms Brown has been treated for myasthenia gravis for several of accidental exposures to toxic amounts of pesticides. The most years. She reports to the emergency department complain- toxic of these drugs (eg, parathion) can be rapidly fatal if exposure ing of recent onset of weakness of her hands, diplopia, and difficulty swallowing. She may be suffering from a change in is not immediately recognized and treated. After standard protec- response to her myasthenia therapy, that is, a cholinergic or tion of vital signs (see Chapter 58), the antidote of first choice a myasthenic crisis. Which of the following is the best drug is the antimuscarinic agent atropine, but this drug has no effect for distinguishing between myasthenic crisis (insufficient on the nicotinic signs of toxicity. Nicotinic toxicity is treated by therapy) and cholinergic crisis (excessive therapy)? regenerating active cholinesterase. Immediately after binding to (A) Atropine cholinesterase, most organophosphate inhibitors can be removed (B) Edrophonium from the enzyme by the use of regenerator compounds such as (C) Physostigmine (D) Pralidoxime pralidoxim (see Chapter 8), and this may reverse both nicotinic (E) Pyridostigmine and muscarinic signs. If the enzyme-phosphate binding is allowed to persist, however, aging (a further chemical change) occurs and regenerator drugs can no longer remove the inhibitor. Treatment is described in more detail in Chapter 8.  CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 65 4. A crop duster pilot has been accidentally exposed to a high 10. Which of the following is the primary second-messenger pro- concentration of a highly toxic agricultural organophosphate cess in the contraction of the ciliary muscle when focusing on insecticide. If untreated, the cause of death from such expo- near objects? sure would probably be (A) cAMP (cyclic adenosine monophosphate) (A) Cardiac arrhythmia (B) DAG (diacylglycerol) (B) Gastrointestinal bleeding (C) Depolarizing influx of sodium ions via a channel (C) Heart failure (D) IP3 (inositol 1,4,5-trisphosphate) (D) Hypotension (E) NO (nitric oxide) (E) Respiratory failure 5. Mr Green has just been diagnosed with dysautonomia (chronic idiopathic autonomic insufficiency). You are consid- ering different therapies for his disease. Pyridostigmine and neostigmine may cause which one of the following in this patient? (A) Bronchodilation (B) Cycloplegia (C) Diarrhea (D) Irreversible inhibition of acetylcholinesterase (E) Reduced gastric acid secretion 6. Parasympathetic nerve stimulation and a slow infusion of bethanechol will each (A) Cause ganglion cell depolarization (B) Cause skeletal muscle end plate depolarization (C) Cause vasodilation (D) Increase bladder tone (E) Increase heart rate 7. Actions and clinical uses of muscarinic cholinoceptor ago- nists include which one of the following? (A) Bronchodilation (treatment of asthma) (B) Miosis (treatment of glaucoma) (C) Decreased gastrointestinal motility (treatment of diarrhea) (D) Decreased neuromuscular transmission and relaxation of skeletal muscle (during surgical anesthesia) (E) Increased sweating (treatment of fever) 8. Which of the following is a direct-acting cholinomimetic that is lipid-soluble and is used to facilitate smoking cessation? (A) Acetylcholine (B) Bethanechol (C) Neostigmine (D) Physostigmine (E) Varenicline 9. A 3-year-old child is admitted to the emergency department after taking a drug from her parents’ medicine cabinet. The signs suggest that the drug is an indirect-acting cholinomi- metic with little or no CNS effect and a duration of action of about 2–4 h. Which of the following is the most likely cause of these effects? (A) Acetylcholine (B) Bethanechol (C) Neostigmine (D) Physostigmine (E) Pilocarpine 66 PART II Autonomic Drugs SKILL KEEPER ANSWER: DRUG METABOLISM (SEE CHAPTER 4) The esters acetylcholine and methacholine are hydrolyzed by acetylcholinesterase. Hydrolytic drug metabolism reactions are classified as phase I. CHECKLIST When you complete this chapter, you should be able to: ❑ List the locations and types of acetylcholine receptors in the major organ systems (CNS, autonomic ganglia, eye, heart, vessels, bronchi, gut, genitourinary tract, skeletal muscle, exocrine glands). ❑ Describe the second messengers involved and the effects of acetylcholine on the major organs. ❑ List the major clinical uses of cholinomimetic agonists. ❑ Describe the pharmacodynamic differences between direct-acting and indirect- acting cholinomimetic agents. ❑ List the major pharmacokinetic differences of the direct- and indirect-acting cholinomimetics. ❑ List the major signs and symptoms of (1) organophosphate insecticide poisoning and (2) acute nicotine toxicity.  DRUG SUMMARY TABLE: Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs. Clinical and Other Subclass Mechanism of Action Applications Pharmacokinetics Toxicities, Interactions Direct-acting, muscarinic agonists Bethanechol Activates muscarinic (M) receptors Bladder and bowel atony, for Oral, IM activity All parasympathomimetic effects: cyclo- 3 and DAG example, after surgery or spinal Poor lipid solubility: does not spasm, diarrhea, urinary urgency, plus cord injury enter CNS vasodilation, reflex tachycardia, and Duration: 0.3–2 h sweating Pilocarpine - Sjögren’s syndrome (increases Oral, IM activity Similar to bethanechol but may cause vate EPSP via M receptors in ganglia Good lipid solubility, topical vasoconstriction via ganglionic effect (causes miosis, cyclospasm) activity in eye Muscarine Same as bethanechol Alkaloid found in mushrooms Low lipid solubility but readily Mushroom poisoning of fast-onset type absorbed from gut Direct-acting, nicotinic agonists Nicotine Smoking cessation (also used as High lipid solubility, absorbed by Generalized ganglionic stimulation: hyper- opens Na+-K+ channels in ganglia and insecticide) all routes tension, tachycardia, nausea, vomiting, neuromuscular end plates diarrhea Major overdose: convulsions, paralysis, used as gum or transdermal patch coma Duration: 4–6 h Varenicline A partial agonist at N receptors Smoking cessation High lipid solubility, oral activity Hypertension, sweating, sensory dis- turbance, diarrhea, polyuria, menstrual disturbance Succinylcholine N-receptor agonist, moderately Muscle relaxation Highly polar, used IV Initial muscle spasms and postoperative pain selective for neuromuscular end (see Chapter 27) plate (NM receptors) butyrylcholinesterase Indirect-acting, alcohol Edrophonium Reversal of NM block by nondepo- Increased parasympathetic effects, espe- of endogenously released Ach - 5–10 min cially nausea, vomiting, diarrhea, urinary thenia gravis urgency Indirect-acting, carbamates Neostigmine Like edrophonium plus small direct Reversal of NM block, treatment of Moderately polar but orally active Like edrophonium but longer duration nicotinic agonist action myasthenia Pyridostigmine Like edrophonium Treatment of myasthenia Moderately polar but orally active Like edrophonium but longer duration Physostigmine Like edrophonium Reversal of severe atropine poison- - Like edrophonium but longer duration plus CNS effects: seizures glaucoma (topical) (Continued ) 67 68 DRUG SUMMARY TABLE: Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs. (Continued ) Clinical and Other Subclass Mechanism of Action Applications Pharmacokinetics Toxicities, Interactions Indirect-acting, organophosphates Parathion Like edrophonium Insecticide only Highly lipid-soluble Duration: days to weeks all parasympathetic effects plus muscle paralysis and coma Malathion Like edrophonium Insecticide and scabicide (topical) Highly lipid-soluble but metabo- Much safer insecticide than parathion Duration: days lized to inactive products in mam- mals and birds Sarin, tabun, others Like parathion Like parathion but more rapid Rapidly lethal action Indirect-acting, for Alzheimer’s disease Rivastigmine, Cholinesterase inhibition plus vari- Alzheimer’s disease Nausea, vomiting galantamine, done- able other poorly understood effects 1.5–70 h pezil; tacrine is obsolete ACh, acetylcholine; DAG, diacylglycerol; EPSP, excitatory postsynaptic potential; IP 3 , inositol-1,4,5-trisphosphate.  8 C H A P T E R Cholinoceptor Blockers & Cholinesterase Regenerators The cholinoceptor antagonists consist of 2 subclasses based on cholinesterase regenerators, are not receptor blockers but rather their spectrum of action (ie, block of muscarinic versus nico- are chemical antagonists of organophosphate acetylcholinester- tinic receptors). These drugs are pharmacologic antagonists or ase (AChE) inhibitors. inverse agonists (eg, atropine). A third, special, subgroup, the Anticholinergic drugs Cholinesterase regenerators Antimuscarinic Antinicotinic Ganglion Neuromuscular M1-selective Nonselective Oximes blockers blockers (pirenzepine) (atropine) (pralidoxime) (hexamethonium) (tubocurarine) MUSCARINIC ANTAGONISTS Atropine is the prototypical nonselective muscarinic blocker. This alkaloid is found in Atropa belladonna and many other A. Classification and Pharmacokinetics plants. Because it is a tertiary amine, atropine is relatively Muscarinic antagonists can be subdivided according to their lipid-soluble and readily crosses membrane barriers. The drug selectivity for specific M receptors or their lack of such selectivity. is well distributed into the CNS, the eye, and other organs. It Although the division of muscarinic receptors into subgroups is well is eliminated partially by metabolism in the liver and partially documented (Chapters 6 and 7), only 2 distinctly receptor-selective unchanged in the urine; half-life is approximately 2 h; and dura- M1 antagonists have reached clinical trials (eg, pirenzepine, telenz- tion of action of normal doses is 4–8 h except in the eye (see epine, neither of which is used in the United States). However, as Drug Summary Table). noted later, a few agents in use in the United States are somewhat In ophthalmology, topical activity (the ability to enter the selective for the M3 subtype. Most of the antimuscarinic drugs in eye after conjunctival administration) and duration of action use are relatively nonselective. The muscarinic blockers can also are important in determining the usefulness of several anti- be subdivided on the basis of their primary clinical target organs muscarinic drugs (see Clinical Uses). Similar ability to cross (central nervous system [CNS], eye, bronchi, or gastrointestinal and lipid barriers is essential for the agents used in parkinsonism. genitourinary tracts). Drugs used for their effects on the CNS or the In contrast, the drugs used for their antisecretory or antispastic eye must be sufficiently lipid-soluble to cross lipid barriers. A major actions in the gut, bladder, and bronchi are often selected for determinant of this property is the presence or absence of a per- minimum CNS activity; these drugs may incorporate quater- manently charged (quaternary) amine group in the drug molecule nary amine groups to limit penetration through the blood– because charged molecules are less lipid-soluble (see Chapter 1). brain barrier. 69 70 PART II Autonomic Drugs High-Yield Terms to Learn Anticholinergic A drug that blocks muscarinic or nicotinic receptors, but commonly used to mean antimuscarinic Antimuscarinic A drug that blocks muscarinic but not nicotinic receptors Atropine fever Hyperthermia induced by antimuscarinic drugs; caused mainly by inhibition of sweating Atropine flush Marked cutaneous vasodilation of the arms and upper torso and head by toxic doses of antimus- carinic drugs, especially atropine; mechanism unknown Cholinesterase regenerator A chemical antagonist that binds the phosphorus of organophosphates and displaces AChE Cycloplegia Paralysis of accommodation; inability to focus on close objects Depolarizing blockade Flaccid skeletal muscle paralysis caused by persistent depolarization of the neuromuscular end plate Miotic A drug that constricts the pupil Mydriatic A drug that dilates the pupil Nondepolarizing blockade Flaccid skeletal muscle paralysis caused by blockade of the nicotinic receptor and prevention of end plate depolarization Parasympatholytic, A drug that reduces the effects of parasympathetic nerve stimulation, usually by blockade of the parasympathoplegic muscarinic receptors of autonomic effector tissues B. Mechanism of Action D. Clinical Uses Although several are inverse agonists, muscarinic blocking agents The muscarinic blockers have several useful therapeutic applications act like competitive (surmountable) pharmacologic antagonists; in the CNS, eye, bronchi, gut, and urinary bladder. These uses are their blocking effects can be overcome by increased concentrations listed in the Drug Summary Table at the end of this chapter. of muscarinic agonists. C. Effects TABLE 8–1 Effects of muscarinic blocking drugs. The peripheral actions of muscarinic blockers are mostly predictable Organ Effect Mechanism effects derived from cholinoceptor blockade (Table 8–1). These include the ocular, gastrointestinal, genitourinary, and secretory CNS Sedation, anti-motion Block of muscarinic sickness action, antipar- receptors, several effects. The CNS effects are less predictable. CNS effects seen at kinson action, amnesia, subtypes therapeutic concentrations include sedation, reduction of motion delirium sickness, and, as previously noted, reduction of some of the signs of Eye Cycloplegia, mydriasis Block of M3 receptors parkinsonism. Cardiovascular effects at therapeutic doses include an Bronchi Bronchodilation, espe- Block of M3 receptors initial slowing of heart rate caused by central effects or blockade of cially if constricted inhibitory presynaptic muscarinic receptors on vagus nerve endings. Gastrointestinal Relaxation, slowed peri- Block of M1, M3 These are followed by the tachycardia and decreased atrioventricular tract stalsis, reduced salivation receptors conduction time that would be predicted from blockade of post- Genitourinary Relaxation of bladder Block of M3 and pos- synaptic muscarinic receptors in the sinus node. M1-selective agents tract wall, urinary retention sibly M1 receptors (not currently available in the United States) may be somewhat Heart Initial bradycardia, espe- Tachycardia from cially at low doses, then block of M2 receptors selective for the gastrointestinal tract. tachycardia in the sinoatrial node Blood vessels Block of muscarinic vaso- Block of M3 receptors dilation; not manifest on endothelium of unless a muscarinic ago- vessels nist is present SKILL KEEPER: DRUG IONIZATION Glands Marked reduction of Block of M1, M3 (SEE CHAPTER 1) salivation; moderate receptors reduction of lacrimation, The pKa of atropine, a weak base, is 9.7. What fraction of atro- sweating; less reduction pine (an amine) is in the lipid-soluble form in urine of pH 7.7? of gastric secretion The Skill Keeper Answer appears at the end of the chapter. Skeletal muscle None  CHAPTER 8 Cholinoceptor Blockers & Cholinesterase Regenerators 71 1. CNS—Scopolamine is standard therapy for motion sickness; 1. Predictable toxicities—Antimuscarinic actions lead to sev- it is one of the most effective agents available for this condition. A eral important and potentially dangerous effects. Blockade of transdermal patch formulation is available. Benztropine, biperiden, thermoregulatory sweating may result in hyperthermia or atro- and trihexyphenidyl are representative of several antimuscarinic pine fever (“hot as a pistol”). This is the most dangerous effect of agents used in parkinsonism. Although not as effective as levodopa the antimuscarinic drugs in children and is potentially lethal in (see Chapter 28), these agents may be useful as adjuncts or when infants. Sweating, salivation, and lacrimation are all significantly patients become unresponsive to levodopa. Benztropine is some- reduced or stopped (“dry as a bone”). Moderate tachycardia is times used parenterally to treat acute dystonias caused by first- common, and severe tachycardia or arrhythmias are common with generation antipsychotic medications. large overdoses. In the elderly, important toxicities include acute angle-closure glaucoma and urinary retention, especially in men 2. Eye—Antimuscarinic drugs are used to cause mydriasis, as with prostatic hyperplasia. Constipation and blurred vision are indicated by the origin of the name belladonna (“beautiful lady”) common adverse effects in all age groups. from the ancient cosmetic use of extracts of the Atropa belladonna plant to dilate the pupils. They also cause cycloplegia and prevent 2. Other toxicities—Toxicities not predictable from peripheral accommodation. In descending order of duration of action, these autonomic actions include CNS and cardiovascular effects. CNS drugs are atropine (>72 h), homatropine (24 h), cyclopentolate toxicity includes sedation, amnesia, and delirium or hallucina- (2–12 h), and tropicamide (0.5–4 h). These agents are all well tions (“mad as a hatter”); convulsions may also occur. Central absorbed from the conjunctival sac into the eye. muscarinic receptors are probably involved. Other drug groups with antimuscarinic effects, for example, tricyclic antidepres- 3. Bronchi—Parenteral atropine has long been used to reduce sants, may cause hallucinations or delirium in the elderly, who airway secretions during general anesthesia. Ipratropium is a qua- are especially susceptible to antimuscarinic toxicity. At very high ternary antimuscarinic agent used by inhalation to promote bron- doses, intraventricular conduction may be blocked; this action is chodilation in asthma and chronic obstructive pulmonary disease probably not mediated by muscarinic blockade and is difficult to (COPD). Although not as efficacious as β agonists, ipratropium is treat. Dilation of the cutaneous vessels of the arms, head, neck, less likely to cause tachycardia and cardiac arrhythmias in sensitive and trunk also occurs at these doses; the resulting “atropine flush” patients. It has very few antimuscarinic effects outside the lungs (“red as a beet”) may be diagnostic of overdose with these drugs. because it is poorly absorbed and rapidly metabolized. Tiotropium The mechanism is unknown. is an analog with a longer duration of action. Aclidinium is a newer long-acting antimuscarinic drug available in combination with a 3. Treatment of toxicity—Treatment of toxicity is usually long-acting β2-adrenoceptor agonist for the treatment of COPD. symptomatic. Severe tachycardia may require cautious administra- tion of small doses of physostigmine. Hyperthermia can usually be 4. Gut—Atropine, methscopolamine, and propantheline were managed with cooling blankets or evaporative cooling. 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 (Chapter 16) and proton pump inhibitors (Chapter 59), F. Contraindications and they cause far more frequent and severe adverse effects. The The antimuscarinic agents should be used cautiously in infants M1-selective inhibitor pirenzepine is available in Europe for the treat- because of the danger of hyperthermia. The drugs are relatively ment of peptic ulcer. Muscarinic blockers can also be used to reduce contraindicated in persons with glaucoma, especially the closed- cramping and hypermotility in transient diarrheas, but drugs such as angle form, and in men with prostatic hyperplasia. diphenoxylate and loperamide (Chapters 31, 59) are more effective. 5. Bladder—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, fes- oterodine, and propiverine are slightly selective for M3 receptors and are promoted for the treatment of stress incontinence. 6. Cholinesterase inhibitor intoxication—Atropine, given parenterally in large doses, reduces the muscarinic signs of poi- soning with AChE inhibitors. Pralidoxime (see below) is used to regenerate active AChE. E. Toxicity A traditional mnemonic for atropine toxicity is “Dry as a bone, hot as a pistol, red as a beet, mad as a hatter.” This description reflects both predictable antimuscarinic effects and some unpredictable actions.  72 PART II Autonomic Drugs TABLE 8–2 Effects of ganglion-blocking drugs. Organ Effects 1. A 27-year old compulsive drug user injected a drug he thought was methamphetamine, but he has not developed CNS Antinicotinic action may include reduction of any signs of methamphetamine action. He has been admitted nicotine craving and amelioration of Tourette’s to the emergency department and antimuscarinic drug over- syndrome (mecamylamine only) dose is suspected. Probable signs of atropine overdose include Eye Moderate mydriasis and cycloplegia which one of the following? (A) Gastrointestinal smooth muscle cramping Bronchi Little effect; asthmatic patients may note some (B) Increased heart rate bronchodilation (C) Increased gastric secretion (D) Pupillary constriction Gastrointestinal Marked reduction of motility, constipation may tract be severe (E) Urinary frequency Genitourinary tract Reduced contractility of the bladder; impair- 2. Which of the following is the most dangerous effect of bel- ment of erection (parasympathetic block) and ladonna alkaloids in infants and toddlers? ejaculation (sympathetic block) (A) Dehydration (B) Hallucinations Heart Moderate tachycardia and reduction in force (C) Hypertension and cardiac output at rest; block of exercise- (D) Hyperthermia induced changes (E) Intraventricular heart block Vessels Reduction in arteriolar and venous tone, dose- 3. Which one of the following can be blocked by atropine? dependent reduction in blood pressure; ortho- (A) Decreased blood pressure caused by hexamethonium static hypotension usually marked (B) Increased blood pressure caused by nicotine Glands Reductions in salivation, lacrimation, sweating, (C) Increased skeletal muscle strength caused by neostigmine and gastric secretion (D) Tachycardia caused by exercise (E) Sweating caused by exercise Skeletal muscle No significant effect Questions 4–5. Two new synthetic drugs (X and Y) are to be studied for their cardiovascular effects. The drugs are given to three CHOLINESTERASE REGENERATORS anesthetized animals while the blood pressure is recorded. The first animal has received no pretreatment (control), the second has Pralidoxime is the prototype cholinesterase regenerator. These received an effective dose of a long-acting ganglion blocker, and chemical antagonists contain an oxime group, which has an the third has received an effective dose of a long-acting muscarinic antagonist. extremely high affinity for the phosphorus atom in organophos-phate insecticides. Because the affinity of the oxime group for phosphorus exceeds the affinity of the 4. Drug X caused a 50 mm Hg rise in mean blood pressure in enzyme-active site for phosphorus, these agents are able to the control animal, no blood pressure change in the ganglion- blocked animal, and a 75 mm mean blood pressure rise in bind the inhibitor and dis-place the enzyme if aging has not the atropine-pretreated animal. Drug X is probably a drug occurred. The active enzyme is thus regenerated. Pralidoxime, similar to the oxime currently available in the United States, is used to (A) Acetylcholine treat patients exposed to high doses of organophosphate AChE (B) Atropine inhibitor insecticides, such as parathion, or to nerve gases. It is (C) Epinephrine not recommended for use in carbamate AChE inhibitor (D) Hexamethonium overdosage. (E) Nicotine  CHAPTER 8 Cholinoceptor Blockers & Cholinesterase Regenerators 73 5. The net changes in heart rate induced by drug Y in these 10. Which one of the following drugs has a very high affinity for experiments are shown in the following graph. the phosphorus atom in parathion and is often used to treat life-threatening insecticide toxicity? (A) Atropine + 50% No blocker Ganglion Muscarinic (B) Benztropine (C) Bethanechol Percent change in heart rate blocker blocker (D) Botulinum (E) Cyclopentolate Y Y (F) Neostigmine 0 (G) Pralidoxime Y – 50% Drug Y is probably a drug similar to (A) Acetylcholine (B) Edrophonium (C) Hexamethonium (D) Nicotine (E) Pralidoxime 6. A 30-year-old man has been treated with several autonomic drugs for 4 weeks. He is now admitted to the emergency department showing signs of drug toxicity. Which of the following signs would distinguish between an overdose of a ganglion blocker versus a muscarinic blocker? (A) Cycloplegia (B) Dry skin in a warm environment (C) Miosis (D) Postural hypotension (E) Tachycardia 7. Which of the following is an accepted therapeutic indication for the use of antimuscarinic drugs? (A) Atrial fibrillation (B) Botulinum poisoning (C) Chronic obstructive pulmonary disease (COPD) (D) Glaucoma (E) Postoperative urinary retention 8. Which of the following is an expected effect of a therapeutic dose of an antimuscarinic drug? (A) Decreased cAMP (cyclic adenosine monophosphate) in cardiac muscle (B) Decreased DAG (diacylglycerol) in salivary gland tissue (C) Increased IP3 (inositol trisphosphate) in intestinal smooth muscle (D) Increased potassium efflux from smooth muscle (E) Increased sodium influx into the skeletal muscle end plate 9. Which one of the following drugs causes vasodilation that can be blocked by atropine? (A) Benztropine (B) Bethanechol (C) Botulinum toxin (D) Cyclopentolate (E) Edrophonium (F) Neostigmine (G) Pralidoxime 74 PART II Autonomic Drugs 7. Atrial fibrillation and other arrhythmias are not responsive to antimuscarinic agents. Botulinum poisoning is associ- SKILL KEEPER ANSWER: DRUG IONIZATION ated with parasympathetic blockade. Parkinson’s disease, (SEE CHAPTER 1) not Huntington’s, is partially responsive to antimuscarinic drugs. Antimuscarinic drugs tend to cause urinary retention and may precipitate or exacerbate glaucoma. Bronchospasm The pKa of atropine is 9.7. According to the Henderson- is mediated in part by vagal outflow in many patients with Hasselbalch equation, COPD and in some with asthma. The answer is C. Log (protonated / unprotonated) = pK a - pH 8. Muscarinic M1 and M3 receptors mediate increases in IP3 and DAG in target tissues (intestine, salivary glands). M2 recep- Log (P / U) = 9.7 - 7.7 tors (heart) mediate a decrease in cAMP and an increase in Log (P / U) = 2 potassium permeability. Antimuscarinic agents block these effects. The answer is B. P / U = antilog (2) 9. Bethanechol (Chapter 7) causes vasodilation by directly acti- = 100 /1 vating muscarinic receptors on the endothelium of blood vessels. This effect can be blocked by atropine. Indirectly Therefore, about 99% of the drug is in the protonated form, acting agents (AChE inhibitors) do not typically cause vaso- 1% in the unprotonated form. Since atropine is a weak base, dilation because the endothelial receptors are not innervated and acetylcholine is not released at this site. Pralidoxime is a it is the unprotonated form that is lipid soluble. Therefore, distracter in this answer list. The answer is B. about 1% of the atropine in the urine is lipid soluble. 10. Pralidoxime has a very high affinity for the phosphorus atom in organophosphate insecticides. The answer is G. CHECKLIST When you complete this chapter, you should be able to: ❑ Describe the effects of atropine on the major organ systems (CNS, eye, heart, ves- sels, bronchi, gut, genitourinary tract, exocrine glands, skeletal muscle). ❑ List the signs, symptoms, and treatment of atropine overdose. ❑ List the major clinical indications and contraindications for the use of muscarinic antagonists. ❑ Describe the effects of the ganglion-blocking nicotinic antagonists. ❑ List one antimuscarinic agent promoted for each of the following uses: to produce mydriasis and cycloplegia; to treat parkinsonism, asthma, bladder spasm, and the muscarinic toxicity of insecticides ❑ Describe the mechanism of action and clinical use of pralidoxime.  CHAPTER 8 Cholinoceptor Blockers & Cholinesterase Regenerators 75 DRUG SUMMARY TABLE: Cholinoceptor Blockers & Cholinesterase Regenerators Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Antimuscarinic, nonselective Atropine Competitive pharmaco- Lipid-soluble All parasympatholytic effects logic antagonist (inverse antidote for cholinester- Duration: 2–4 h except plus sedation, delirium, agonist) at all M receptors ase inhibitor toxicity in eye: ≥72 h hyperthermia, flushing Benztropine, others: antiparkinsonism; oral and parenteral Dicyclomine, glycopyrrolate: oral, parenteral for gastrointestinal applications Homatropine, cyclopentolate, tropicamide: topical ophthalmic use to produce mydriasis, cycloplegia Ipratropium, tiotropium, aclidinium: inhaled for asthma, chronic obstructive pulmonary disease Oxybutynin: oral, transdermal, promoted for urinary urgency, incontinence Scopolamine: anti-motion sickness via transdermal patch Trospium: oral, for urinary urgency Antimuscarinic, selective Darifenacin, fesoterodine, Like atropine, but Urinary urgency, Oral Excessive parasympatholytic solifenacin, tolterodine modest selectivity for incontinence Duration: 12–24 h effects M3 receptors Pirenzepine, telenzepine Significant M1 selectivity Peptic disease (not Oral Excessive parasympatholytic available in USA) effects Antinicotinic ganglion blockers Hexamethonium Selective block of NN Obsolete; was used for Oral, parenteral Block of all autonomic receptors hypertension effects Trimethaphan: IV only, short-acting; was used for hypertensive emergencies and controlled hypotension Mecamylamine: oral, enters CNS; investigational use for smoking cessation Antinicotinic neuromuscular blockers See Chapter 27 AChE regenerator Pralidoxime Chemical antagonist of Organophosphate Parenteral Muscle weakness organophosphates poisoning