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59 Cards in this Set
- Front
- Back
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What is the endogenous ligand for all cholinergic receptors?
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Acetylcholine
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Cholinergic agonists are also known as what?
Cholinergic antagonists are also known as what? |
Parasympathomimetics
Parasympatholytics |
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Cholinergic agonists are active at which synapses?
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Parasympathetic neuroeffector junctions (muscarinic)
Presynaptic autoreceptors (muscarinic) Ganglia (nicotinic) CNS active through muscarinic and nicotinic if agonist crosses BBB |
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What are the two classes of cholinergic agonists?
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Direct acting: acts directly on cholinergic receptors
Indirect acting: alters enzymes that degrade or synthesize ACh (mostly acetylcholinesterase) |
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What are the three classes of direct acting cholinergic agonists?
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Choline esters
Plant alkaloids Synthetics |
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What are the two classes of indirect acting cholinergic agonists?
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Reversible AChE inhibitors
Irreversible AChE inhibitors |
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Name 3 choline esters
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ACh
Bethanechol Carbachol |
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Name 3 plant alkaloids
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Muscarine
Nicotine Pilocarpine |
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Name 1 direct acting synthetic cholinergic agonist
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Cevimeline
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Name 5 reversible AChE inhibitors
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Edrophonium
Neostigmine Physostigmine Pyridostigmine Donepezil & Related Drugs |
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Name 4 irreversible AChE inhibitors
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Echothiophate
Isoflurophate Malathion Parathion |
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Section on Direct Acting Cholinergic Receptor Agonists
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none
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Direct Acting Cholinergic Agonists: General Effects
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Poorly absorbed from GI tract (except for nicotine)
Lack of specificity causes widespread side effects |
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Direct Acting Cholinergic Agonists: Common Side Effects
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Cardiac Effects (M2): Decrease impulse formation in SA node, slow heart rate, slow conduction, increase PR interval. Mimics vagal stimulation
GI & Urinary Effects (M3): Salivary stimulation, increase in gastric secretion, increase smooth muscle contraction (except sphincters), increase motility, diarrhea, cramps, urinary incontinence CNS arousal (if specific drug penetrates CNS) Side effects profile limits pharmacological use |
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Direct Acting Cholinergic Agonists: Cardiovascular Effects
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Vasodilation
↓ cardiac rate (negative chronotropic effect) ↓ rate of conduction at SA and AV nodes (negative dromotrophic effects) ↓ force of contraction (negative inotropic effects) Barorecptor response may dampen these – slightly or at low doses |
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Direct Acting Cholinergic Agonists: Genitourinary Effects
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↑ tone, contraction, and secretion
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Direct Acting Cholinergic Agonists: Ocular Effects
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↑ lacrimal gland secretion
Stimulate contraction of iris sphincter and ciliary muscles Pupillary constriction (miosis) Accomodation for close focus |
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Direct Acting Cholinergic Agonists: Drugs: ACh: general considerations
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Limited clinical use
Rapid hydrolysis by acetylcholinesterase (AChE) or butylcholinesterase (BChE) Systemic admin ↓ BP (M3 receptors on vasculature) but requires large dose |
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Direct Acting Cholinergic Agonists: Drugs: ACh: indications
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Cataract Surgery: miosis after lens extraction
Diagnostic angiography (no longer method of choice): Intracoronary injection → vasodilation through muscarinic receptors in vascular endothelium, if normal → Vasospastic effect caused if muscarinic receptors on smooth muscle are effected which is diagnostic for Vasospastic Angina |
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Direct Acting Cholinergic Agonists: Drugs: ACh: effects of small and large IV doses
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Small Dose: transient ↑ in BP (Butyrlcholinesterase in plasma degrades ACh rapidly), Reflex tachycardia
Large dose: large dose required to produce bradycardia or AV block, Vasodilation (not long lasting) |
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Direct Acting Cholinergic Agonists: Drugs: Pilocarpine: general considerations
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Plant alkaloid (Pilocarpus)
Well absorbed after ocular or oral admin, much less potent than ACh Lowers intraocular pressure |
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Direct Acting Cholinergic Agonists: Drugs: Pilocarpine: indications
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Second line drug for chronic open-angle glaucoma
Also used for acute angle closure glaucoma Oral admin for xerostomia: stimulates salivation (sialogogue) at very low doses with minimal side effects due to high sensitivity of salivary glands to muscarinic stimulation, mouth sprays |
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Direct Acting Cholinergic Agonists: Drugs: Pilocarpine: adverse effects
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Decreased night vision, decreased distance focus, flushing, headache, dizziness, GI disturbances, rhinitis
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Direct Acting Cholinergic Agonists: Bethanechol & Carbachol: general considerations
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Choline esters of carbamic acid
Resistant to AChE Short duration of action, hrs. |
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Direct Acting Cholinergic Agonists: Bethanechol: indications
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Muscarinic specific
Stimulates bladder or GI smooth muscle without affecting HR Tx of urinary retention in absence of obstruction (post op, post partum) Some benefit in partial sensory or motor paralysis of bladder SQ doses for acute retention → never given IV d/t hypotension & bradycardia Withdrawn when normal voiding returns |
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Direct Acting Cholinergic Agonists: Carbachol: indications
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NOT muscarinic specific
Chronic open angle glaucoma Usually only if poor response to pilocarpine Sometimes for miosis in opthalmic surgery |
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Direct Acting Cholinergic Agonists: Cevimeline: general considerations
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Synthetic
Muscarinic selectivity Preferable to pilocarpine – longer half life and side effects are much milder |
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Direct Acting Cholinergic Agonists: Cevimeline: indications
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Tx of xerostomia and dry eyes
Radiation of head & neck Sjogren’s Syndrome |
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Direct Acting Cholinergic Agonists: Cevimeline: adverse effects
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Sweating, nausea, visual disturbances, miosis – usually mild and less than other drugs in this class
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Direct Acting Cholinergic Agonists: Muscarine and Nicotine: general considerations
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Plant Alkaloids
Muscarine: present in the mushrooms Inocybe, Clitocybe, Amanita. No clinical use Nicotine: found in Nicotiniana plant, used in smoking cessation |
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Direct Acting Cholinergic Agonists: Myceitism
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Mushroom poisoning
S/S develop within 30-60 min of ingestion Due to excess cholinergic agonism (for Inocybe, Clitocybe – NOT Amanita) |
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Direct Acting Cholinergic Agonists: Myceitism s/s
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Salivation, lacrimation, N/V/cramps
Headache, visual disturbance, hallucination Bronchospasm, bradycardia, hypotension → shock |
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Direct Acting Cholinergic Agonists: Myceitism Tx
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Atropine 1-2 mg IM every 30 min, but depends on mushroom species
Epi for cardiovascular or bronchospasm |
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Direct Acting Cholinergic Agonists: Contraindications
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Asthma
Cardiac Arrhythmias Cardiac Insufficiency (hypotension can reduce coronary blood flow) Peptic Ulcer Hyperthyroidism |
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Section on Indirect Acting Cholinergic Receptor Agonists
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Anticholinesterases
Inhibit AChE → More ACh at synapse (or neuromuscular junction), ↑ neurotransmission Reversible → short acting Irreversible → longer acting |
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Indirect Acting Cholinergic Agonists: General effects
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Indirect muscarinic AND nicotinic agonists
Stimulation of muscarinic responses at autonomic effectors Stimulation, then depression or paralysis of autonomic ganglia or skeletal muscle (via nicotinic – receptor) All depends on dose, agent, and route of administration, therapeutic doses are usually very small |
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Indirect Acting Cholinergic Agonists: CNS effects
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Stimulation of cholinergic CNS sites
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Indirect Acting Cholinergic Agonists: Ocular effects
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Local application = miosis
Pinpoint pupils, but can still decrease some in response to light Decreased intraocular pressure |
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Indirect Acting Cholinergic Agonists: GI effects
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↑ contraction
↑ secretion |
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Indirect Acting Cholinergic Agonists: Neuromuscular effects
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Contraction
Increased [ACh] at synapse Reverses effects of non-depolarizing neuromuscular blocking agents |
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Reversible Indirect Acting Cholinergic Agonists: Neostigmine, Physostigmine, Pyridostigmine: general
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Carbamic Acid esters
Only physostigmine crosses BBB Binds to AChE similar to ACh → Slowly hydrolyzed by enzyme Prevents breakdown of endogenous ACh for several hrs |
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Reversible Indirect Acting Cholinergic Agonists: Neostigmine, Physostigmine, Pyridostigmine: indications
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Myasthenia gravis: excessive doses cause cholinergic crisis, usually combined with corticosteroids or immunosuppressants
Curare Toxicity: neostigmine or pyridostigmine Postop Urinary Retention & abdominal distention: neostigmine Glaucoma: physostigmine Atropine OD or OD of other antimuscarinic drug |
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Reversible Indirect Acting Cholinergic Agonists: Edrophonium: general
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Reversibly binds to negatively charged site on AChE
Not a substrate for enzyme Blocks ACh hydrolysis Binding is reversible, renal excretion, short duration of action (10 min) |
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Reversible Indirect Acting Cholinergic Agonists: Edrophonium: indications
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Differential dx of myasthenia gravis which is an autoimmune disease in which Ab destroy nicotinic ACh receptors in skeletal musc → severe muscle fatigue, esp. in muscles of face, eyes, throat, neck
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Reversible Indirect Acting Cholinergic Agonists: Edrophonium: edriphonium test
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IV injection of edriphonium, look for rapid improvement in weakness (+ for myasthenia)
Fasiculation generally occurs if NOT myasthenia Definitive + dx is when NAChR Ab appear in blood |
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Reversible Indirect Acting Cholinergic Agonists: Edrophonium: myasthenic and cholinergic crisis
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Myasthenic crisis: severe ACh deficiency → edrophonium used to improve
Cholinergic crisis: excessive dose of AChE inhibitor results in ACh excess → prolonged muscle depolarization produces depolarizing blockade → muscle paralysis. Resolve by lowering the dose of AChE inihbitor |
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Reversible Indirect Acting Cholinergic Agonists: Donazepil, et al: general
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Donepezil, Galantamine, Rivastigmine
Centrally acting, reversible AChE inhibitors Cross the BBB Increase ACh in CNS cholinergic synapses |
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Reversible Indirect Acting Cholinergic Agonists: Donazepil, et al: indications
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Treatment of Alzheimer’s Disease: pts have loss of cholinergic neurons in CNS
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Reversible Indirect Acting Cholinergic Agonists: Adverse effects
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Result from excessive cholinergic stimulation
DUMBBELSS (salivation, flushing, ↓ BP, N/V/D, abd pain, bronchospasm) Atropine is antidotal |
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Irreversible Indirect Acting Cholinergic Agonists: General
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Highly lipid soluble organophosphates (readily absorbed from skin, eyes, mucosa)
Few therapeutic agents Common in pesticides and warfare agents (Soman, Tabun, Sarin, VX) Widespread use in pesticides → frequent cause of accidental poisoning |
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Irreversible Indirect Acting Cholinergic Agonists: MOA
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Covalently binds to the active site of AChE and is slowly hydrolyzed
Recovery usually requires synthesis of new enzymes (days) "Aging" further stabilizes the bond |
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Irreversible Indirect Acting Cholinergic Agonists: S/S
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All the effects of muscarinic and nicotinic activation
DUMBBELSS Depolarizing neuromuscular blokade and paralysis d/t excessive nicotinic stimulation Seizure, resp depression, and coma from CNS effects |
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Irreversible Indirect Acting Cholinergic Agonists: Signs of toxicity
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Parasympathetic overstimulation
Respiratory or vapor exposure: resp and ocular effects occur in minutes GI or cutaneous exposure: delayed effects. Sweating and localized fasciculation if skin is exposed Advanced effects: bradycardia, hypovolemia, paralysis, CNS effects Time to death: 5 min - 24 h (untreated), depending on route of exposure. Primary COD is resp failure, secondary is cardiac complications |
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Irreversible Indirect Acting Cholinergic Agonists: Clinical use
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Ocular conditions (not the drugs of choice though): echothiophate or isoflurophate to tx chronic glaucoma refractory to other tx. Used for long duration (24h) control of IOP. Tx of strabismus (esotropia).
Tx of head lice (Pediculosis capitis): malathion 0.5% lotion to kill lice and ova |
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Irreversible Indirect Acting Cholinergic Agonists: Intermediate syndrome
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Delayed symptoms of 1-2 days
Persistant low blood AChE levels Severe muscle weakness Requires continued treatment |
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Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: general
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Decontaminate pt
CV and resp support Cholinergic Receptor Antagonist: atropine (high dose, 2-4 mg to start, may need to repeat every 5-10 min – may need up to 200 mg/day or more) Diazepam for convulsions Treat any shock |
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Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: Pralidoxime
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Pralidoxime (2-PAM, 1-2 G IV, repeated PRN): regenerates AChE by breaking the covalent bond between the enzyme and the phosphoryl group of the toxin
2-PAM does not enter CNS Less effect for newer agents since aging is more rapid |
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Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: Butylcholinesterase
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IV admin
Scavenges the toxin Circulating toxin binds BChE first Preserves AChE Time is again, of the essence |
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Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: Lipid partitioning
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Some agents are highly lipophilic → partition into body fat
Symptoms recur after initial treatment Treatment may need to be continued 1+ week |
