PHARMA-A-DRUGS-ACTING-ON-PNS-MEDTRANS2027.docx.pdf

PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 1 INDIRECT-ACTING DRUG ACTING ON THE PARASYMPATHETIC NERVOUS...

PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 1 INDIRECT-ACTING DRUG ACTING ON THE PARASYMPATHETIC NERVOUS SPECTRUM SYSTEM DRUG PHARMACOKINETIC FUNCTION OF ACTION* CHOLINOCEPTOR-ACTIVATING AND Alcohol, quaternary amine CHOLINESTERASE-INHIBITING DRUGS Poor lipid solubility Edrophonium Cholinomimetics – drugs with acetylcholine-like e ects; Not orally active 2 major subgroups (based on mode of action) Duration of action: 5-15 min ○ Direct – bind to acetylcholine receptors subdivided Carbamate on the basis of their spectrum of action Quaternary amine Neostigmine Poor lipid solubility Whether they act on muscarinic or nicotinic Orally active cholinoceptors. Duration of action: 30 min-2h or more ○ Indirect – inhibit cholinesterase enzyme Carbamate Acetylcholine – prototype that acts directly at Tertiary amine muscarinic and nicotinic receptors Physostigmine Good lipid solubility Neostigmine – prototype for the indirect-acting Orally active cholinesterase inhibitors B Duration of action: 30 min-2h Carbamate Pyridostigmine Like neostigmine, but longer duration of action (4-8h) Organophosphate Echothiophate Moderate lipid solubility Duration of action: 2-7 days Organophosphate High lipid solubility Parathion Duration of action: 7-30 days Insecticide Organophosphate Sarin Very high lipid solubility Nerve gas *B, both M & N; M, muscarinic; N, nicotinic DIRECT-ACTING CHOLINOMIMETIC AGONISTS The specificity of receptors (spectrum of action) may be Acetylcholine, methacholine, added in exams. In direct acting, Acetylcholine and Carbachol carbachol, bethanechol are both; Nicotine and Varenicline specifically only bind to Choline esters Nicotinic receptors. Varenicline is used for reduction of Note: Has “chol” in their names cravings in Nicotine addiction. Others are muscarinic receptors. Naturally occurring muscarine, pilocarpine, nicotine, alkaloids lobeline CLASSIFICATION Newer drugs are occasionally introduced for special MUSCARINIC AGONISTS NICOTINIC AGONISTS applications Parasympathomimetic Act on both ganglionic Members di er in their spectrum of action (amount of (mimic the actions of or neuromuscular muscarinic versus nicotinic stimulation) and parasympathetic nerve cholinoceptors; limited pharmacokinetics → influence their clinical use stimulation) in addition agonist selectivity. to other e ects Can have ganglion SOME CHOLINOMIMETICS: SPECTRUM OF ACTION & 5 subgroups of muscarinic escalation e ects - they PHARMACOKINETICS receptors have been can stimulate both the DIRECT-ACTING identified; the muscarinic sympathetic and SPECTRUM agonists available for parasympathetic, DRUG PHARMACOKINETIC FUNCTION clinical use activate them especially in toxicity OF ACTION* Rapidly hydrolyzed by cholinesterase non-selectively where it has e ects on (ChE) both systems. Acetylcholine B Duration of action 5-30s Few slightly selective muscarinic and nicotinic Poor lipid solubility antagonists are available (see chapter on Resistant to ChE cholinoceptors) Bethanechol M Orally active, poor lipid solubility Duration of action 30 min-2hr Carbachol B Like bethanechol Not an ester, good lipid solubility Pilocarpine M Duration of action30 min-2h Not an ester Nicotine N Duration of action 1-6h High lipid solubility Partial agonist at N receptors Varenicline N High lipid solubility Duration 12-24h FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 2 MOLECULAR MECHANISMS OF ACTION Sphincter muscle of iris Ciliary muscle MUSCARINIC MECHANISM Contraction (miosis) Contraction Muscarinic receptors – G protein-coupled receptors Eye (accommodation for Coupled to the Gq protein → activates near vision) phospholipase C (a membrane-bound enzyme) Cyclospasm release of second messengers: ↓ rate (negative chronotropy) ○ Diacylglycerol (DAG) - modulates protein SA Node ○ But note important reflex response M1 and kinase C (important in secretion) in intact subject M3 ○ Inositol-1,4,5-trisphosphate (IP3) - ↓ contractile force (negative causes the release of calcium from Atria inotropy) intracellular storage smooth muscle Heart ↓ refractory period contraction ↓ conduction velocity (negative Couple to adenylyl cyclase through the AV Node dromotropy) inhibitory Gi protein ↑ refractory period Also couples via the βγ subunit of the G Ventricles Small decrease in contractile force M2 protein to potassium channels (notably in the heart). Blood Dilation via release of EDRF from endothelium Muscarinic agonists promote the opening of vessels potassium channels (Potassium e ux) Bronchi Contraction (Bronchoconstriction) Have roles in the CNS; not major players in Motility Sphincters M4 and ↑smooth muscle ↓tone peripheral organs M5 contraction Relaxation GIT Peristalsis (exception: CHILINOCEPTOR TYPES & THEIR POST RECEPTOR gastroesophageal MECHANISMS sphincter contracts) RECEPTOR G PROTEIN POST RECEPTOR Detrusor TYPE MECHANISMS ↑contraction Urinary Trigone and Sphincter M1, M3, M5 Gq ↑IP3, DAG cascade bladder Relaxation M2, M4 Gi ↓cAMP synthesis Voiding NM, NN None Na+/K+ depolarizing current *cAMP, cyclic adenosine monophosphate Skeletal Activation of neuromuscular end plates *DAG, diacylglycerol muscle Contraction *IP3, inositol-1,4,5-triphosphate Increased secretion (thermoregulatory sweating, Glands lacrimation, salivation, bronchial secretion, (exocrine) NICOTINIC MECHANISM gastrointestinal glands) *Only the direct e ects are indicated; homeostatic responses to these direct Nicotinic acetylcholine receptors (nAChRs) – located on actions may be important. channel protein selective for sodium (Na⁺) and EDRF, endothelium-derived relaxing factor (primarily nitric oxide). potassium (K⁺) Note that vasodilation is not a parasympathomimetic ○ Activation → opens the channel → cell response depolarization due to sodium influx → generates ○ It is not evoked by parasympathetic nerve an excitatory postsynaptic potential (EPSP) → discharge, even though directly acting large enough EPSP → triggers a propagated cholinomimetics cause vasodilation. action potential in the surrounding membrane This vasodilation results from the release of NN (or NG) receptors – Nicotinic receptors on endothelium-derived relaxing factor (EDRF; nitric oxide sympathetic and parasympathetic ganglion neurons and possibly other substances) in the vessels, mediated NM receptors – Nicotinic receptors on neuromuscular by uninnervated muscarinic receptors on the endothelial end plates; di er slightly from NN receptors. cells. Note also that decreased blood pressure evokes the baroreceptor reflex, resulting in strong compensatory TISSUE AND ORGAN EFFECTS sympathetic discharge to the heart. CHOLINOMIMETICS EFFECTS ON MAJOR ORGAN SYSTEMS As a result, injections of small to moderate amounts of ORGAN RESPONSE* direct-acting muscarinic cholinomimetics often cause Complex stimulatory e ects tachycardia, whereas parasympathetic (vagal) nerve Nicotine Physostigmine discharge to the heart causes bradycardia. Elevation of mood, Convulsions, Another e ect seen with cholinomimetic drugs but not alerting, addiction excessive with parasympathetic nerve stimulation is CNS (nicotine-naive concentrations may thermoregulatory (eccrine) sweating; this is a individuals often cause coma sympathetic cholinergic e ect. su er nausea and vomiting on initial exposure) FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 3 Not a parasympathetic response CLINICAL USE Caused by release of Clinical conditions that benefit from increased endothelium-derived relaxing factors cholinergic activity (e.g., nitric oxide) ○ Glaucoma Mediated by uninnervated muscarinic ○ Sjogren’s syndrome (xerostomia, xerophthalmia, receptors on endothelial cells and rheumatoid arthritis) Baroreceptor Reflex ○ Loss of normal PANS activity in the bowel and ○ Decreased blood pressure from bladder (e.g. ileus, postoperative ileus) cholinomimetics triggers Direct-acting nicotinic agonist uses: compensatory sympathetic ○ Smoking cessation (i.e. nicotine gum, patch, discharge (because of the lozenge) vasodilation) → results in ○ Skeletal muscle paralysis (succinylcholine) tachycardia with small/moderate This is agonist but the e ect is similar to Vasodilation & doses of muscarinic antagonist, which favors muscle paralysis. Cholinomimetics cholinomimetics Note: indirect-acting agents are used when increased ○ If a direct acting agent is given, nicotinic activation is needed at the neuromuscular the e ect of vasodilation in the junction (see later discussion on myasthenia gravis) vessel supersedes and the reflex, ○ MG = results to muscle weakness tachycardia occurs. ○ In contrast: Parasympathetic Drugs Used in Glaucoma (vagal) stimulation of the heart causes bradycardia. ○ Direct cholinomimetic agent binds to the non-innervated muscarinic receptors in the endothelium causing vasodilation. This vasodilation triggers the reflex tachycardia. Thermoregulatory Sympathetic cholinergic e ect, not (eccrine) parasympathetic Sweating First line drug that are used for glaucoma are Blood vessels (sympathetic control) → prostaglandin analogues - less adverse e ects and Nicotinic activation leads to higher e cacy vasoconstriction via sympathetic Nicotinic Supplement: postganglionic nerve discharge Ganglionic ○ Pilocarpine - direct acting Gut (parasympathetic control) → Stimulation ○ Physostigmine - indirect acting Nicotinic activation increases motility Nicotine and related neonicotinoids - used as and secretion via parasympathetic insecticides despite reported toxic e ects on bee postganglionic neuron discharge colonies Causes fasciculations and muscle Varenicline - newer nicotinic agonist with partial agonist Nicotinic spasm (contractions) properties; appears to reduce craving in persons Neuromuscular Prolonged activation results in addicted to nicotine through a non-autonomic action. End Plate Activation paralysis (e.g., from nicotine or organophosphate insecticides). TOXICITY The tissue and organ level e ects of nicotinic ganglionic Readily predicted from the general pharmacology of stimulation depend on the autonomic innervation of the acetylcholine organ involved. The blood vessels are dominated by sympathetic MUSCARINIC TOXICITY innervation; therefore, nicotinic receptor activation CNS stimulation (uncommon with choline results in vasoconstriction mediated by sympathetic CNS E ects esters and pilocarpine) postganglionic nerve discharge. The gut is dominated by parasympathetic control; Miosis (pupil constriction), Spasm of nicotinic drugs increase motility and secretion because Ocular E ects accommodation (eye muscle spasm of increased parasympathetic postganglionic neuron a ecting near vision) discharge. Respiratory Bronchoconstriction (narrowing of Nicotinic neuromuscular end plate activation by E ects airways) direct-acting drugs results in fasciculations and spasm of Gastrointestinal the muscles involved. and Excessive smooth muscle activity Prolonged activation (long term e ect) results in Genitourinary paralysis, which is an important hazard of exposure to E ects nicotine-containing and organophosphate insecticides. FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 4 Increased secretion from sweat glands, Liver transplant - treatment in severe Increased airways, gastrointestinal tract, and cases Secretory Activity lacrimal glands Renal proximal tubular lesions seen in Transient bradycardia (slow heart rate) severe poisoning Cardiovascular followed by reflex tachycardia when given E ects as IV bolus or otherwise NICOTINIC TOXICITY Vasodilation Occurs alongside other systemic e ects Ganglionic stimulation and blood Muscarine and related alkaloids Neuromuscular end plate depolarization (Inocybe species, Amanita muscaria) - ⬇ cause short-duration poisoning Fasciculations (nausea, vomiting, diarrhea) ⬇ Mushroom Amanita phalloides - causes more Paralysis Poisoning dangerous poisoning, with (to be discussed in the topic on skeletal muscle relaxants) vomiting/diarrhea followed by hepatic Stimulation (including convulsions) followed and renal necrosis (due to amanitin CNS Toxicity by depression and phalloidin [RNA polymerase Nicotine in small doses (i.e. via smoking, vaping) – inhibitors], not muscarinic agonists) strongly addicting PARASYMPATHETIC STIMULATION Mushrooms of genera Inocybe, Clitocybe, and INDIRECT-ACTING AGONISTS Omphalotus → contain muscarine CLASSIFICATION AND PROTOTYPES ○ Consumption causes diarrhea, sweating, Indirect-Acting Cholinomimetics - act as salivation, and lacrimation acetylcholinesterase (AChE) inhibitors ○ Due to stimulation of parasympathetic receptors MAJOR CHEMICAL CLASSES Carbamic acid esters Prototype – neostigmine (Carbamates) Prototype - parathion (important Phosphoric acid esters insecticide) (Organophosphates) Can be used to diagnose Inocybe sororia Clitocybe fragrans Omphalotus olivascens myasthenia gravis The only one clinically useful EXCITATORY AMINO ACID (EAAs) Alcohols member is edrophonium; very short Amanita muscaria (fly agaric) and A. pantherina duration of action (panther agaric) – fungi that contain ibotenic acid (glutamate receptor agonist) and possibly its derivative MECHANISM OF ACTION muscimol (GABAA agonist) Carbamate and organophosphate inhibitors bind to ○ Variable e ects: central nervous system depression, cholinesterase and undergo prompt hydrolysis ataxia, hysteria, and hallucinations; myoclonic Alcohol portion is released quickly; acidic portion twitching and seizures can develop (carbamate ion or phosphate ion) is released slowly Slow release of the acidic portion prevents INHIBITION OF RNA POLYMERASE cholinesterase from binding and hydrolyzing endogenous Nonedible mushrooms – most cause GI distress; most acetylcholine → amplification of acetylcholine e ects are not life-threatening wherever the neurotransmitter is released ○ Amanita phalloides – most deaths are due to liver Duration of Action damage ○ Edrophonium – binds to the cholinesterase active ○ A. ocreata – “death angel”; equally dangerous site and prevents acetylcholine access for a short duration (5–15 min). NON-EDIBLE MUSHROOMS - 2 TOXIC CHEMICALS ○ Carbamates – hydrolyzed and released by Cyclic heptapeptide; combines with actin cholinesterase over 2–8 hours in muscle cells to interfere with muscle ○ Organophosphates – form a highly stable PHALLOIDIN phosphate complex (i.e. aging) release takes days function → contributes to diarrhea (develops 10 to 12 h after ingestion) to weeks Recovery Mechanism Readily absorbed, bicyclic peptides ○ Recovery from organophosphate inhibition depends Alpha-amanitin – most toxic; has a strong on the synthesis of new cholinesterase enzyme a nity for hepatocytes → binds to RNA AMATOXINS polymerase II → inhibit protein synthesis 3rd day of ingestion: serious clinical signs manifest FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 5 EFFECTS Gravis. Increase the concentration, half-life, and ○ So, there will be rapid improvement in muscle actions of acetylcholine at synapses where weakness it is physiologically released. ○ But it will also go back to its initial presentation which Implication: indirect agents have is muscle weakness. muscarinic and nicotinic e ects While in a cholinergic crisis, edrophonium will worsen depending on the organ system under the muscle weakness, since the level of acetylcholine is consideration: already high and upon administration of Edrophonium it CHOLINESTERASE will further increase the levels of acetylcholine. ○ Muscarinic e ects in organs like INHIBITION Not all patients with muscle weakness are not because of the heart, lungs, and glands ○ Nicotinic e ects in skeletal a cholinergic crisis. muscles and autonomic ganglia Minimal e ects at uninnervated sites where acetylcholine is not normally released ○ E.g., vascular endothelial cells) AMPLIFICATION OF CHOLINERGIC Main therapeutic application ACTIVITY E.g., neostigmine, physostigmine, pyridostigmine, ambenonium More commonly prescribed than organophosphates. Key role in the treatment of CARBAMATES myasthenia gravis (MG) ○ Autoimmune disorder; treatment may also involve thymectomy and immunosuppressants E.g., carbaryl Used as insecticides In Medicine: ORGANO Malathion – scabicide PHOSPHATES Metrifonate - antihelmintic agent For rapid reversal of nondepolarizing neuromuscular blockade Used in the diagnosis of myasthenia gravis Helps di erentiate between myasthenic crisis and cholinergic crisis in myasthenia gravis patients: (Full table on the last page) Myasthenia Crisis Cholinergic Crisis Edrophonium Edrophonium further TOXICITY improves muscle weakens muscle Organophosphates (e.g., parathion) can cause toxic strength strength exposure, often via pesticides Cholinergic crisis – can mimic the ○ Toxicity will manifest both muscarinic and nicotinic. EDROPHONIUM muscle weakness of myasthenic crisis ○ Drugs that should be administered must be atropine → di erentiation is challenging without and acetylcholine esterase regenerator. edrophonium ○ Mushroom poisoning: only atropine should be given, Not widely used today since but since this also has nicotinic toxicity it should Myasthenia Gravis can be diagnosed also be addressed. through history. Accidental exposure can be rapidly fatal if not treated Organophosphate poisoning can be immediately di erentiated from Myasthenia gravis ○ The most toxic of these drugs (eg, parathion) can be based on the history of the patient. rapidly fatal if exposure is not immediately Both cholinergic crisis and Myasthenia recognized and treated. gravis manifest weak muscle First steps in treatment – protect vital signs as per weakness. standard medical protocols CHOLINERGIC CRISIS VS. MYASTHENIA GRAVIS: First-line Antidote: Atropine (an antimuscarinic agent) Upon administration of Edrophonium, since it is an ○ Treats muscarinic e ects but does not a ect acetylcholinesterase inhibitor, it will increase the levels of nicotinic toxicity acetylcholine which is what we need for Myasthenia FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 6 Nicotinic toxicity requires regeneration of active cholinesterase ○ Immediately after binding to cholinesterase, most organophosphate inhibitors can be removed from the enzyme by the use of regenerator compounds. ○ Pralidoxime removes the organophosphate from cholinesterase; can reverse both nicotinic and muscarinic signs of toxicity ○ If the enzyme-phosphate bond **ages** (undergoes further chemical change), pralidoxime becomes ine ective MUSCARINIC ANTAGONISTS Organophosphates - extensively used in agriculture as CLASSIFICATION AND PHARMACOKINETICS insecticides and antihelminthic agents because of their Note: Most of the muscarinic antagonists are usually toxicity and short persistence in the environment non-selective in action Malathion and dichlorvos – relatively safe in humans Classification by receptor selectivity due to rapid metabolism to inactive products in ○ Some muscarinic antagonists are selective for mammals and birds, but not in insects specific M receptor subtypes Prodrugs ○ Most clinically used antimuscarinic drugs are ○ Malathion → malaoxon nonselective ○ Parathion → paraoxon M1 Selective antagonists Signs and symptoms of poisoning are similar to receptor Examples: Pirenzepine, telenzepine (reached direct-acting agents, with some exceptions: clinical trials; not used in the U.S.) ○ Vasodilation - late and uncommon e ect M3 Selective antagonists ○ Bradycardia - more common than tachycardia receptor A few agents in the U.S. have some selectivity ○ CNS stimulation - convulsions, respiratory, and for the M3 subtype cardiovascular depression; occurs with Subdivision by target organ - based on their clinical organophosphate and **physostigmine** target organs overdose ○ CNS (e.g., Parkinson’s disease, motion sickness) Similar for both direct- and indirect-acting ○ Eye (e.g., to induce mydriasis) cholinomimetics; ○ Bronchi (e.g., to treat COPD) Cholinesterase inhibitors amplify nicotinic and ○ Gastrointestinal and genitourinary tracts (e.g., to muscarinic actions treat overactive bladder) * More nicotinic manifestations are observed* Lipid solubility determines tissue penetration ○ Note: depends on agent and type of exposure (toxic ○ Drugs a ecting the CNS or eye need to be vs therapeutic) lipid-soluble to cross lipid barriers ○ In patients with MG, nicotinic e ects may be In contrast, if you want the drug’s action to be notable, but muscarinic e ects predominate more localized, the drug’s structure may be systemic toxicity. altered to maintain their polarity so they have DUMBBELSS – all are primarily muscarinic EXCEPT E a less chance to cross the membrane and D Diarrhea, defecation leave the area. U Urination ○ Presence of a quaternary amine group decreases M Miosis lipid solubility, reducing CNS penetration B Bronchospasm ATROPINE B Bradycardia Prototype non selective muscarinic blocker Excitation Tertiary amine → relatively lipid-soluble E (CNS and skeletal muscle nicotinic receptor → followed by Membrane permeability - readily crosses membrane post-excitatory depression or block) barriers → well-distributed in the CNS, eye, and other L Lacrimation organs S Salivation Source Atropa belladonna and other plants S Sweating Elimination Partially metabolized in the liver; Partially excreted unchanged in the urine CHOLINOCEPTOR BLOCKERS AND CHOLINESTERASE Half-life Approximately 2 hours REGENERATOR Duration of 4–8 hours for normal doses; prolonged Cholinoceptor antagonists Action duration in the eye ○ 2 subclasses based on spectrum of action (i.e. muscarinic versus nicotinic receptors) Topical activity (ability to enter the eye after ○ Pharmacologic antagonists or inverse agonists (eg, conjunctival administration) and duration of action - key atropine) for determining the usefulness of antimuscarinic drugs in Cholinesterase regenerators - chemical antagonists of the eye organophosphate acetylcholinesterase (AChE) inhibitors FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 7 ○ Atropine eye drops that have a long duration of Receptor Drug Action Clinical Use action cause prolonged mydriasis Specificity ○ Although some drugs like Tropicamide which have a Ophthalmology short duration of action cause mydriasis only for a Bradycardia few minutes. Tropicamide is used by Atropine Organophosphate ophthalmologists to observe the retina Nonselective poisoning ○ Note: Atropine is also used in eye surgeries since Inverse (M1, M2, M3) Motion sickness we need the pupils to be dilated Scopolamine Agonist Nausea Lipid solubility - important for drugs used in COPD Parkinson's disease (CNS-acting drugs) Ipratropium Asthma ○ Drugs that we need for treating Parkinson’s disease M3 COPD are those which block the e ect of Acetylcholine. Tiotropium (Long-acting) Asthma ○ Generally, what we want are drugs that will Gastric ulcers promote dopamine e ects and block acetylcholine Pirenzepine M1 selective (not used in US) e ects. (Since the problem with Parkinson’s is the Competitive Telenzepine Gastric ulcers balance between dopamine and acetylcholine) Antagonist Darifenacin ○ ↓ Dopamine & ↑ Acetylcholine M3 selective Overactive bladder Solifenacin ○ Medications: Atropine & Scopolamine can cross the blood-brain Drugs that enhance the e ect of dopamine barrier Drugs that would reduce the e ect of Ipratropium & Tiotropium contains quaternary acetylcholine ammonium compounds When you block the Muscarinic receptors in the CNS, it Example: can be used as an adjunct in controlling the symptoms of ○ Atropine acts as an inverse agonist and can induce Parkinson’s disease tachycardia in patients with bradycardia. For ○ Symptoms such as tremors, rigidity, problem with instance, if a pharmacologic agent used causes gait bradycardia, atropine may be administered to If to be used for antisecretory or antispastic actions (gut, reverse that e ect. bladder, bronchi) - should have minimal CNS activity to avoid side e ects; EFFECTS ○ Incorporation of quaternary amine groups limits penetration through the blood-brain barrier EFFECTS OF MUSCARINIC BLOCKING DRUGS ORGAN EFFECT MECHANISM MECHANISM OF ACTION Sedation Anti-motion sickness Several are inverse agonists Block of muscarinic action ○ Inverse agonists - will produce an e ect that is CNS Antiparkinson action receptors, several opposite of the e ect of the endogenous agonist. subtypes Amnesia Act like competitive (surmountable) pharmacologic Delirium antagonists Cycloplegia Eye ○ Competitive antagonist - will only prevent the Mydriasis Block of M3 receptors agonist binding to its receptor but does not have Bronchodilation Bronchi intrinsic activity. It normalizes the e ector cell’s (especially if constricted) function to its baseline level and as a result, the Relaxation Block of M1, M3 activity level remains equivalent to that observed GIT Slowed peristalsis receptor Reduced salivation without agonist binding, producing no Relaxation of bladder activity/e ect. Genitourinary Block of M3 and wall ○ Blocking e ects can be overcome by increased tract possibly M1 receptors Urinary retention concentrations of muscarinic agonists. Initial bradycardia Tachycardia from Inverse agonist VS Competitive antagonists: Heart (especially at low doses, block of M2 receptors ○ Both of them will prevent the binding of the then tachycardia) in the sinoatrial node endogenous agonist because both of them act Block of Muscarinic competitively. They will compete with the same vasodilation Block on M3 receptors binding site which is the same muscarinic receptor. Blood vessels (not manifest unless a on endothelium of ○ Inverse agonist - opposite e ect muscarinic agonist is vessels present) ○ Competitive antagonists - prevent binding without Marked reduction of intrinsic activity salivation Moderate reduction of Block of M1, M3 Glands lacrimation, sweating receptor Less reduction of gastric secretion Skeletal muscle None FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 8 The peripheral actions of muscarinic blockers are mostly Therefore, about 99% of the drug is in the protonated predictable e ects derived from cholinoceptor blockade form, 1% in the unprotonated form. Since atropine is a (Table 8–1). weak base, it is the unprotonated form that is lipid These include the ocular, gastrointestinal, genitourinary, soluble. Therefore, about 1% of the atropine in the urine and secretory e ects. The CNS e ects are less is lipid soluble. predictable. CNS e ects seen at therapeutic concentrations include sedation, reduction of motion sickness, and, as previously noted, reduction of some of CLINICAL USE the signs of parkinsonism. Muscarinic blockers have several useful therapeutic Cardiovascular e ects at therapeutic doses include an applications in the CNS, eye, bronchi, gut, and urinary initial slowing of heart rate caused by central e ects or bladder. 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. M1-selective agents (not currently available in the United States) may be somewhat selective for the gastrointestinal tract. PERIPHERAL AND CNS ACTIONS OF MUSCARINIC BLOCKERS Mostly predictable; stem from cholinoceptor blockade Eye: Mydriasis (pupil dilation), cycloplegia (Full table on the last page) (loss of accommodation). Peripheral GIT: Reduced gastric motility and Scopolamine - standard therapy for E ects secretions. motion sickness; available in a transdermal GUT: Relaxation of the bladder, leading to patch formulation urinary retention. Antimuscarinic agents for Parkinsonism Decreased salivation, sweating, and other ○ Benztropine, biperiden, and secretions. trihexyphenidyl are commonly used. Less predictable ○ Less e ective than levodopa but may CNS Sedation at therapeutic concentrations. be useful as adjunct therapy ○ Helpful when patients become Reduction of motion sickness CNS unresponsive to levodopa ○ E.g., scopolamine Benztropine - also used parenterally to Reduction of parkinsonism symptoms treat acute dystonias caused by first-generation antipsychotics At therapeutic doses ○ Anticholinergic Initial bradycardia Mydriasis - the term belladonna ○ Due to central e ects or vagus nerve ("beautiful lady") originates from the ancient inhibition cosmetic use of Atropa belladonna to dilate CVS Subsequent tachycardia and decreased pupils atrioventricular conduction time - due to Cycloplegia - prevents the eye from blockade of postsynaptic muscarinic accommodating to focus on near objects receptors in the sinus node Duration of action (descending order) Eyes M1-Selective Not available in the U.S. ○ Atropine: >72 hours agents May show some selectivity for the GIT ○ Homatropine: 24 hours ○ Cyclopentolate: 2–12 hours ○ Tropicamide: 0.5–4 hours REVIEW M Used in ophthalmic examinations The pKa of atropine, a weak base, is 9.7. What fraction of All agents are well absorbed from the atropine (an amine) is in the lipid-soluble form in urine of conjunctival sac into the eye. pH 7.7? Atropine (parenteral) The pKa of atropine is 9.7. ○ Reduces airway secretions during According to the Henderson- Hasselbalch equation: general anesthesia Log (protonated unprotonated) = pK – pH ○ Used in the treatment of asthma Bronchi Log (P/U) = 9.7 - 7.7 however, systemic symptoms cannot be Log (P/U) = 2 avoided P/U = antilog (2) Ipratropium - Quaternary antimuscarinic = 100/1 agent; administered by inhalation FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 9 ○ Promotes bronchodilation in asthma Flushing or redness of the skin, often and COPD RED AS A BEET resulting from the vasodilation and lack ○ Less e ective than β agonists but has of sweating fewer cardiac side e ects (tachycardia Confusion, delirium, or hallucinations due and arrhythmias) MAD AS A HATTER to central nervous system e ects ○ Limited systemic e ects poor absorption and rapid metabolism CNS e ects are more prominent in the elderly Tiotropium ○ Analog of ipratropium; longer duration PREDICTABLE TOXICITIES of action Due to blockade of thermoregulatory Aclidinium sweating; atropine fever or “HOT AS A ○ Newer, long-acting antimuscarinic HYPERTHERMIA PISTOL” ○ Available in combination with a long-acting β2-adrenoceptor agonist Most dangerous in children and for COPD potentially lethal in infants Atropine, methscopolamine, and Significant reduction or cessation of REDUCED propantheline - once used to reduce acid sweating, salivation, and lacrimation; SECRETIONS secretion in acid-peptic disease; obsolete for “DRY AS A BONE” acid-peptic disease due to: Moderate tachycardia is common; ○ Lower e ectiveness - H2 blockers and CARDIOVASCULAR severe tachycardia or arrhythmias can PPIs are more e ective EFFECTS occur with large overdoses ○ More frequent and severe adverse e ects Acute angle-closure glaucoma; urinary ELDERLY-SPECIFIC Pirenzepine - M1-selective inhibitor retention, particularly in men with GUT TOXICITIES available in Europe for treating peptic ulcers prostatic hyperplasia Muscarinic blockers can reduce cramping COMMON ADVERSE (All ages) and hypermotility in transient diarrhea, but EFFECTS Constipation and blurred vision drugs like diphenoxylate (can cross blood brain barrier) and loperamide (opioid derivatives) are more e ective OTHER TOXICITIES Opioid are drugs used as analgesics but they Sedation, amnesia, and delirium or also act on the receptors of the GIT which hallucinations (“MAD AS A HATTER”); slows down mobility convulsions may also occur; central muscarinic Oxybutynin, tolterodine, and similar agents receptors are probably involved Indications: Other drugs with antimuscarinic e ects (e.g. ○ Reducing urgency in mild cystitis CNS tricyclic antidepressants, 1st generation ○ Reducing bladder spasms after TOXICITY antihistamines) may cause hallucinations or urologic surgery Bladder delirium in the elderly (susceptible to M3 Selective Agents antimuscarinic toxicity) ○ Tolterodine, darifenacin, solifenacin, fesoterodine, and propiverine. Take note that antimuscarinic e ects can ○ Promoted for treating stress also occur in other drugs because not all incontinence drugs have one specific mechanism of action Atropine Blockade of intraventricular conduction; ○ Given parenterally in large doses; probably not mediated by muscarinic blockade Cholinesterase reduces muscarinic signs of poisoning and is di cult to treat Inhibitor CVS with AChE inhibitors Intoxication TOXICITY Pralidoxime Dilation of the cutaneous vessels of the arms, ○ Used to regenerate active AChE (at very high head, neck, and trunk also occurs at these doses) doses; the resulting “Atropine Flush” (“RED AS A TOXICITY BEET”) may be diagnostic of overdose; unknown ANTICHOLINERGIC/ANTIMUSCARINIC OVERDOSE mechanism MANIFESTATIONS Decreased secretion of sweat, saliva, and TREATMENT OF TOXICITY DRY AS A BONE other secretions, leading to dry mouth Usually symptomatic and dry skin Severe tachycardia may require cautious administration Blurred vision and inability to focus on of small doses of physostigmine BLIND AS A BAT near objects due to prolonged pupillary Hyperthermia - cooling blankets or evaporative dilation and cycloplegia cooling Hyperthermia or an increase in body HOT AS A temperature due to decreased sweating PISTOL/HARE and impaired thermoregulation FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 10 CONTRAINDICATIONS ○ Nicotine (gum or patches) Use with caution in infants due to danger of ○ Varenicline (a partial agonist given by mouth) Hyperthermia ○ Mecamylamine (nicotinic ganglion blocker that Relatively contraindicated in: enters the CNS) ○ Persons with glaucoma (especially if closed angle) ○ Shown some benefit in smoking cessation. ○ Men with prostatic hyperplasia Interruption sympathetic control of venous tone ⬇ NICOTINIC ANTAGONISTS Marked venous pooling GANGLION-BLOCKING DRUGS ⬇ Historically used for the management of hypertension, Postural hypotension but the e ects are too severe. Both sympathetic and parasympathetic divisions were blocked, therefore Other toxicities: dry mouth, blurred vision, constipation, cannot be tolerated for long periods. and severe sexual dysfunction → ganglion blockers are Act like competitive pharmacologic antagonists; some rarely used also block the pore of the nicotinic channel itself Among the first successful agents for the treatment of NEUROMUSCULAR-BLOCKING DRUGS hypertension (e.g. Hexamethonium [C6, a prototype], Produce marked skeletal muscle relaxation → important Mecamylamine, and several others) in surgery and in mechanical ventilation of patients Adverse e ects are so severe (i.e. both sympathetic and parasympathetic divisions are blocked; see next table) SKELETAL MUSCLE RELAXANTS → patients were unable to tolerate them for long periods NEUROMUSCULAR Trimethaphan was the ganglion blocker most recently SPASMOLYTIC DRUGS BLOCKERS used in clinical practice, but it too has been almost Provide muscle paralysis to Reduce abnormally abandoned. facilitate surgery or elevated tone caused by ○ It is poorly lipid-soluble, inactive orally, and has a assisted ventilation neurologic dysfunction or short half life. Used primarily for muscle muscle disease ○ It was used intravenously to treat severe relaxation and paralysis top accelerated hypertension (malignant hypertension) facilitate intubation before and to produce controlled hypotension. patient operation ○ These drugs are still used in research. In theory, ganglion-blocking drugs can be used to manage nicotine toxicity DRUG INTERACTION WITH ACH RECEPTOR ON THE SKELETAL MUSCLE END PLATE EFFECTS OF GANGLION-BLOCKING DRUGS ORGAN EFFECTS Anti-Nicotinic action may include reduction CNS of nicotine craving and amelioration of Tourette’s syndrome (Mecamylamine only) Eye Moderate mydriasis and cycloplegia Little e ect; asthmatic patients may note Bronchi some bronchodilation Gastrointestinal Marked reduction of motility, constipation tract may be severe Reduced contractility of the bladder; Genitourinary POSTSYNAPTIC AGENTS - DEPOLARIZING BLOCKERS impairment of erection (Parasympathetic tract Nicotinic agonists (in principle) but clinically used as block) and ejaculation (Sympathetic block) blockers Moderate tachycardia and reduction in Noncompetitive; initially activate receptors, causing Heart force and cardiac output at rest; block of depolarization, but in doing so block further activation exercise-induced changes Act on the motor end-plate like ACh (agonist; increase Reduction in arteriolar and venous tone, the cation permeability of the end-plate); di erence: dose-dependent reduction in blood ○ ACh – released in brief spurts and rapidly Vessels pressure; orthostatic hypotension usually hydrolyzed marked ○ Depolarizing blockers – remain associated with the Reductions in salivation, lacrimation, receptors long enough to cause a sustained Glands sweating, and gastric secretion depolarization and a resulting loss of electrical Skeletal muscle No significant e ect excitability (Phase I) → not reversed by anticholinesterase drugs Recent interest: CNS nicotinic receptors and their role in nicotine addiction and to Tourette’s syndrome FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 11 Repeated/continuous administration→Phase II – Toxicities: end-plate becomes less sensitive to ACh (probably due to ○ GI distress, emesis, muscle pain, hyperKalemia, receptor desensitization) malignant hyperthermia ○ Starts to show tetanic fade; partly reversed by anticholinesterase drugs POSTSYNAPTIC AGENTS - NONDEPOLARIZING BLOCKERS ○ When there is desensitization, you want more NOTE: With “CUR” in its name acetylcholine Competitive antagonists; binds to the nicAChR but does Succinylcholine – the only depolarizing blocker used not activate it clinically because of its rapid onset and short duration of Amount of ACh released by the nerve terminal usually action (approx. 6 minutes) greatly exceeds that required to generate an action ○ Quaternary ammonium compound; must be given potential → 80 – 90% of receptors must be blocked to via IV prevent transmission ○ Rapidly hydrolyzed by plasma cholinesterase; Neuromuscular Junction Block people with a genetic variant of this enzyme may ○ Curare - South American arrow experience a neuromuscular block that lasts for poison; potent neuromuscular hours – PSEUDOCHOLINESTERASE DEFICIENCY blocking agent for skeletal muscle Patient may experience prolonged apnea → paralysis; kills by stopping No e ect on patients with myasthenia gravis (these respiration patients have a decreased number of receptors at the Mechanism: blockade of ACh at end-plate → reduced blocking potency the postsynaptic junction Side e ects Obtained from tropical species ○ Initial spasms – occur prior to paralysis; often result of Strychnos and Chondrodendron in postoperative muscle pain Quaternary ammonium compounds → do not cross the ○ Muscarinic receptor activation – result in blood-brain barrier or placenta bradycardia; prevented by administration of Poorly absorbed orally → must be administered via IV atropine ○ To produce systemic muscle relaxant e ect ○ Potassium release from muscle – result in elevated “Tetanic fade” (non maintained muscle tension during potassium levels; usually a problem only in the case brief nerve stimulation) – seen with some drugs of trauma ○ Explained by the blocking of the presynaptic Succinylcholine - initially causes depolarization and resultant autoreceptors which usually maintain the release of loss of electrical excitability Ach during repeated stimulation This is Phase I of neuromuscular blockade Block can be reversed by anticholinesterases and Phase II is due to receptor desensitization depolarizing drugs Enhanced by myasthenia gravis DEPOLARIZING - SUMMARY Main side e ect: hypotension due to blocking of Nicotinic agonist ganglionic transmission Succinylcholine - typically does not need a reversal Histamine release from mast cells → bronchospasm in agent since it has a short duration of action some patients ○ Short duration of action (3 – 6 mins) after single dose due to rapid metabolism (plasma NON-DEPOLARIZING BLOCKERS OF THE POSTSYNAPTIC cholinesterases/pseudocholinesterases RECEPTORS AT THE NEUROMUSCULAR JUNCTION ○ Some experience prolonged action due to enzyme TUBOCURARINE deficiency (genotypic variation) ≈Duration Histamine Prolonged apnea in Pseudocholinesterase Ganglion block Elimination (mins) release Deficiency 60-120 Partial Sometimes Mainly hepatic Treatment: Prolonged intubation until Other side e ects: Hypersensitivity patient has continuous respiration Anticholinesterase drugs that will increase PANCURONIUM levels of acetylcholine and will now ≈Duration Ganglion Histamine Elimination compete with Succinylcholine for binding (mins) block release with Nicotinic receptor 40-60 X Minimal Mainly renal MOA Other side e ects: End plate is depolarized brief fasciculations Block of muscarinic receptors in the heart → tachycardia prolonged depolarization flaccid paralysis; not GALLAMINE PHASE I ≈Duration Ganglion Histamine reversed by AChE inhibitors (actually increases Elimination phase I) (mins) block release (with continuous infusion: desensitization): Mainly renal Muscle end plate repolarizes but remains blocked 15 X X (avoid in patients PHASE II with renal disease) (similar to nondepolarizing blockade); may be reversed by AChE inhibitors Other side e ects: Block of muscarinic receptors in the heart → tachycardia FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 12 ALCURONIUM ○ A nity of the oxime group for phosphorus >>> ≈Duration Histamine a nity of the enzyme-active site for phosphorus Ganglion block Elimination (mins) release →bind the inhibitor and displace the enzyme if 20 X X Mainly hepatic aging has not occurred → active enzyme is Other side e ects: Dose dependency regenerated VECURONIUM Because the a nity of the oxime group for ≈Duration Histamine phosphorus exceeds the a nity of the Ganglion block Elimination (mins) release enzyme-active site for phosphorus, these 20-30 X X Mainly hepatic agents are able to bind the inhibitor and ATRACURIUM displace the enzyme if aging has not occurred. ≈Duration Histamine ○ Used to treat patients exposed to high doses of Ganglion block Elimination (mins) release organophosphate AChE inhibitor insecticides Degradation in (parathion) or nerve gases plasma at body Pralidoxime 15-30 X Sometimes pH ○ Not recommended for use in carbamate AChE (Hofmann inhibitor over dosage elimination) Because it doesn't have phosphate groups ≈ : approximately Carbamate poisoning (binds to acetylcholinesterase enzyme) → pralidoxime NON-DEPOLARIZING - SUMMARY may bind to phosphate group of D-Tubocurarine acetylcholinesterase → worsening of further ○ Prototype; related drugs vary in PK and PD inhibition of remaining acetylcholinesterases properties (more toxic) Mechanism of action Usually carbamate poisoning may recover ○ Competitive antagonism prevents depolarization by without the needs of pralidoxime acetylcholine (Ach) at the skeletal muscle end plate ○ Carbamates do not undergo aging the need for Reversible by acetylcholinesterase (AChE) pralidoxime is not as critical; the enzyme can be inhibitors reactivated by simply allowing time for the Progressive paralysis: face → limbs → respiratory carbamate to dissociate from the enzyme (i.e. muscles enzyme activity typically recovers without the need No e ects on cardiac and smooth muscles; no CNS for pralidoxime) e ects ○ By giving pralidoxime in carbamate poisoning, Toxicities: there is a risk that it could interfere with the normal ○ Respiratory paralysis and autonomic e ects spontaneous reactivation of acetylcholinesterase by competing for the enzyme's active site (competitive inhibition), potentially delaying recovery. NON-DEPOLARIZING - SPECIFIC DRUGS Atracurium Mivacurium Rapid recovery Very short duration Safe in hepatic or renal Metabolized by plasma impairment cholinesterases Spontaneous inactivation to laudanosine Laudanosine can cause seizures CHOLINESTERASE REGENERATORS Pralidoxime – prototype; chemical antagonist; contain an oxime group which has an extremely high a nity for the phosphorus atom in organophosphate insecticides ○ Pralidoxime are ONLY used for organophosphate poisoning not for carbamate overdose because it binds on the phosphate groups Address both muscarinic and nicotinic toxicity MOA: instead of organophosphate binding to the acetylcholinesterase enzyme, it will bind to pralidoxime → acetylcholinesterase will regenerate → utilize by the body → degradation of acetylcholine (acetyl + choline) FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 13 DRUG SUMMARY TABLE CHOLINOCEPTOR-ACTIVATING & CHOLINESTERASE-INHIBITING DRUGS CLINICAL & SUBCLASS MOA PHARMACOKINETICS TOXICITIES, INTERACTIONS OTHER APPLICATIONS DIRECT-ACTING, MUSCARINIC AGONISTS All parasympathomimetic e ects: Oral, IM activity Activates muscarinic (M) Bladder & bowel atony ○ Cyclospasm, vasodilation Poor lipid solubility Bethanechol receptors (Ex. after surgery/spinal ○ Diarrhea, sweating Does not enter CNS ↑ IP3 & DAG cord injury) ○ Urinary urgency Duration: 0.3-2h ○ Reflex tachycardia Same as bethanechol Sjögren’s syndrome Oral, IM activity Similar to bethanechol but may (↑salivation) Pilocarpine May also activate EPSP via Good lipid solubility cause vasoconstriction via Was used in glaucoma M receptors in ganglia Topical activity in the eye ganglionic e ect (causes miosis, cyclospasm) Alkaloid found in Low lipid solubility but Mushroom poisoning of fast-onset Muscarine Same as bethanechol mushrooms readily absorbed from gut type DIRECT-ACTING, NICOTINIC AGONISTS High lipid solubility Generalized ganglionic Activates all nicotinic (N) Absorbed by all routes stimulation: receptors Smoking cessation (also For smoking cessation, ○ Hypertension, tachycardia Nicotine Opens Na+-K+ channels in used as insecticide) ○ Nausea, vomiting, diarrhea ganglia & neuromuscular usually used as Major overdose: end plates gum/transdermal patch ○ Convulsions, paralysis, coma Duration: 4-6h Hypertension, sweating High lipid solubility A partial agonist at N Sensory disturbance Varenicline Smoking cessation Oral activity receptors Diarrhea, polyuria DUration: ~12h Menstrual disturbance N-receptor agonist Initial muscle spasms & post Highly polar Moderately selective for operative pain Succinylcholine Muscle relaxation Used IV neuromuscular end plate Prolonged action in persons with Duration: 5-10 min (NM receptors) abdominal butyrylcholinesterase INDIRECT-ACTING, ALCOHOL Reversal of NM block by Increased parasympathetic Inhibitor of cholinesterase Highly polar nondepolarizing drugs e ects, especially nausea, Edrophonium Amplifier of endogenously Used IV Diagnosis of vomiting, diarrhea, urinary released Ach Duration: 5-10 min myasthenia gravis urgency INDIRECT-ACTING, CARBAMATES Like edrophonium plus Reversal of NM block Moderately polar Like edrophonium but longer Neostigmine small direct nicotinic Treatment of Orally active duration agonist action Myasthenia Duration: 2-4h Moderately polar Treatment of Like edrophonium but longer Pyridostigmine Like edrophonium Orally active Myasthenia duration Duration: 4-8h Reversal of severe Lipid soluble atropine poisoning (IV) Like edrophonium but longer Can be used topically in the Physostigmine Like edrophonium Occasionally used in duration plus CNS e ects: eye acute glaucoma seizures Duration: 2-4h (topical) INDIRECT-ACTING, ORGANOPHOSPHATES Highly dangerous insecticide Insecticide only Causes all parasympathetic Parathion Like edrophonium Highly lipid soluble Duration: days to weeks e ects plus muscle paralysis and coma Highly lipid-soluble but Insecticide & scabicide metabolized to inactive Much safer insecticide than Malathion Like edrophonium (topical) products in mammals & parathion Duration: days birds Sarin, tabun, Nerve gasses Like parathion but more Like parathion Rapidly lethal others Terrorist threat rapid action FEU NRMF MEDICINE BATCH 2027 © MED TRANS 2027  PHARMACOLOGY A LECTURE | DR. ABRAHAM DANIEL C. CRUZ, MD, MSc, FPSECP 14 INDIRECT-ACTING, FOR ALZHEIMER’S DISEASE Rivastigmine, Cholinesterase inhibition galantamine, LLipid soluble, enter CNS plus variable other poorly ALzheimer’s disease Nausea, vomiting donepezil; Half-lives: 1.5-70h understood e ects Tacril is obsolete *ACh (acetylcholine), DAG (diacylglycerol), EPSP (excitatory postsynaptic potential, IP3 (inositol-1,4,5-triphosphate) DRUG SUMMARY TABLE CHOLINOCEPTOR- BLOCKERS & CHOLINESTERASE REGENERATORS SUBCLASS MOA CLINICAL APPLICATIONS PHARMACOKINETICS TOXICITIES, INTERACTIONS ANTIMUSCARINIC, NONSELECTIVE Competitive Mydriatic, cycloplegic Lipid-soluble All parasympatholytic e ects plus pharmacologic antagonist Antidote for Atropine Duration:2-4h except sedation, delirium, hyperthermia, (inverse agonist) at all M cholinesterase inhibitor in eye: ≥72h flushing receptors toxicity Benztropine, others: anti-parkinsonism; oral & parenteral Dicyclomine, glycopyrrolate: oral, parenteral for gastrointestinal applications Homatropine, cyclopentolate, tropicamide: topical ophthalmic use to produce mydriasis, cycloplegia Ipratropium, tiotropium, aclidinium: inhaled for asthma, COPD Oxybutynin: oral, transdermal, promoted for urinary urgency, incontinence Scopolamine: anti-motion sickness via transdermal patch Trospium: oral, f