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59 Cards in this Set

  • Front
  • Back
What is the endogenous ligand for all cholinergic receptors?
Acetylcholine
Cholinergic agonists are also known as what?
Cholinergic antagonists are also known as what?
Parasympathomimetics
Parasympatholytics
Cholinergic agonists are active at which synapses?
Parasympathetic neuroeffector junctions (muscarinic)
Presynaptic autoreceptors (muscarinic)
Ganglia (nicotinic)
CNS active through muscarinic and nicotinic if agonist crosses BBB
What are the two classes of cholinergic agonists?
Direct acting: acts directly on cholinergic receptors
Indirect acting: alters enzymes that degrade or synthesize ACh (mostly acetylcholinesterase)
What are the three classes of direct acting cholinergic agonists?
Choline esters
Plant alkaloids
Synthetics
What are the two classes of indirect acting cholinergic agonists?
Reversible AChE inhibitors
Irreversible AChE inhibitors
Name 3 choline esters
ACh
Bethanechol
Carbachol
Name 3 plant alkaloids
Muscarine
Nicotine
Pilocarpine
Name 1 direct acting synthetic cholinergic agonist
Cevimeline
Name 5 reversible AChE inhibitors
Edrophonium
Neostigmine
Physostigmine
Pyridostigmine
Donepezil & Related Drugs
Name 4 irreversible AChE inhibitors
Echothiophate
Isoflurophate
Malathion
Parathion
Section on Direct Acting Cholinergic Receptor Agonists
none
Direct Acting Cholinergic Agonists: General Effects
Poorly absorbed from GI tract (except for nicotine)
Lack of specificity causes widespread side effects
Direct Acting Cholinergic Agonists: Common Side Effects
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
Direct Acting Cholinergic Agonists: Cardiovascular Effects
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
Direct Acting Cholinergic Agonists: Genitourinary Effects
↑ tone, contraction, and secretion
Direct Acting Cholinergic Agonists: Ocular Effects
↑ lacrimal gland secretion
Stimulate contraction of iris sphincter and ciliary muscles
Pupillary constriction (miosis)
Accomodation for close focus
Direct Acting Cholinergic Agonists: Drugs: ACh: general considerations
Limited clinical use
Rapid hydrolysis by acetylcholinesterase (AChE) or butylcholinesterase (BChE)
Systemic admin ↓ BP (M3 receptors on vasculature) but requires large dose
Direct Acting Cholinergic Agonists: Drugs: ACh: indications
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
Direct Acting Cholinergic Agonists: Drugs: ACh: effects of small and large IV doses
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)
Direct Acting Cholinergic Agonists: Drugs: Pilocarpine: general considerations
Plant alkaloid (Pilocarpus)
Well absorbed after ocular or oral admin, much less potent than ACh
Lowers intraocular pressure
Direct Acting Cholinergic Agonists: Drugs: Pilocarpine: indications
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
Direct Acting Cholinergic Agonists: Drugs: Pilocarpine: adverse effects
Decreased night vision, decreased distance focus, flushing, headache, dizziness, GI disturbances, rhinitis
Direct Acting Cholinergic Agonists: Bethanechol & Carbachol: general considerations
Choline esters of carbamic acid
Resistant to AChE
Short duration of action, hrs.
Direct Acting Cholinergic Agonists: Bethanechol: indications
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
Direct Acting Cholinergic Agonists: Carbachol: indications
NOT muscarinic specific
Chronic open angle glaucoma
Usually only if poor response to pilocarpine
Sometimes for miosis in opthalmic surgery
Direct Acting Cholinergic Agonists: Cevimeline: general considerations
Synthetic
Muscarinic selectivity
Preferable to pilocarpine – longer half life and side effects are much milder
Direct Acting Cholinergic Agonists: Cevimeline: indications
Tx of xerostomia and dry eyes
Radiation of head & neck
Sjogren’s Syndrome
Direct Acting Cholinergic Agonists: Cevimeline: adverse effects
Sweating, nausea, visual disturbances, miosis – usually mild and less than other drugs in this class
Direct Acting Cholinergic Agonists: Muscarine and Nicotine: general considerations
Plant Alkaloids
Muscarine: present in the mushrooms Inocybe, Clitocybe, Amanita. No clinical use
Nicotine: found in Nicotiniana plant, used in smoking cessation
Direct Acting Cholinergic Agonists: Myceitism
Mushroom poisoning
S/S develop within 30-60 min of ingestion
Due to excess cholinergic agonism (for Inocybe, Clitocybe – NOT Amanita)
Direct Acting Cholinergic Agonists: Myceitism s/s
Salivation, lacrimation, N/V/cramps
Headache, visual disturbance, hallucination
Bronchospasm, bradycardia, hypotension → shock
Direct Acting Cholinergic Agonists: Myceitism Tx
Atropine 1-2 mg IM every 30 min, but depends on mushroom species
Epi for cardiovascular or bronchospasm
Direct Acting Cholinergic Agonists: Contraindications
Asthma
Cardiac Arrhythmias
Cardiac Insufficiency (hypotension can reduce coronary blood flow)
Peptic Ulcer
Hyperthyroidism
Section on Indirect Acting Cholinergic Receptor Agonists
Anticholinesterases
Inhibit AChE → More ACh at synapse (or neuromuscular junction), ↑ neurotransmission
Reversible → short acting
Irreversible → longer acting
Indirect Acting Cholinergic Agonists: General effects
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
Indirect Acting Cholinergic Agonists: CNS effects
Stimulation of cholinergic CNS sites
Indirect Acting Cholinergic Agonists: Ocular effects
Local application = miosis
Pinpoint pupils, but can still decrease some in response to light
Decreased intraocular pressure
Indirect Acting Cholinergic Agonists: GI effects
↑ contraction
↑ secretion
Indirect Acting Cholinergic Agonists: Neuromuscular effects
Contraction
Increased [ACh] at synapse
Reverses effects of non-depolarizing neuromuscular blocking agents
Reversible Indirect Acting Cholinergic Agonists: Neostigmine, Physostigmine, Pyridostigmine: general
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
Reversible Indirect Acting Cholinergic Agonists: Neostigmine, Physostigmine, Pyridostigmine: indications
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
Reversible Indirect Acting Cholinergic Agonists: Edrophonium: general
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)
Reversible Indirect Acting Cholinergic Agonists: Edrophonium: indications
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
Reversible Indirect Acting Cholinergic Agonists: Edrophonium: edriphonium test
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
Reversible Indirect Acting Cholinergic Agonists: Edrophonium: myasthenic and cholinergic crisis
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
Reversible Indirect Acting Cholinergic Agonists: Donazepil, et al: general
Donepezil, Galantamine, Rivastigmine
Centrally acting, reversible AChE inhibitors
Cross the BBB
Increase ACh in CNS cholinergic synapses
Reversible Indirect Acting Cholinergic Agonists: Donazepil, et al: indications
Treatment of Alzheimer’s Disease: pts have loss of cholinergic neurons in CNS
Reversible Indirect Acting Cholinergic Agonists: Adverse effects
Result from excessive cholinergic stimulation
DUMBBELSS (salivation, flushing, ↓ BP, N/V/D, abd pain, bronchospasm)
Atropine is antidotal
Irreversible Indirect Acting Cholinergic Agonists: General
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
Irreversible Indirect Acting Cholinergic Agonists: MOA
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
Irreversible Indirect Acting Cholinergic Agonists: S/S
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
Irreversible Indirect Acting Cholinergic Agonists: Signs of toxicity
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
Irreversible Indirect Acting Cholinergic Agonists: Clinical use
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
Irreversible Indirect Acting Cholinergic Agonists: Intermediate syndrome
Delayed symptoms of 1-2 days
Persistant low blood AChE levels
Severe muscle weakness
Requires continued treatment
Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: general
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
Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: Pralidoxime
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
Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: Butylcholinesterase
IV admin
Scavenges the toxin
Circulating toxin binds BChE first
Preserves AChE
Time is again, of the essence
Irreversible Indirect Acting Cholinergic Agonists: Tx of organophosphate poisoning: Lipid partitioning
Some agents are highly lipophilic → partition into body fat
Symptoms recur after initial treatment
Treatment may need to be continued 1+ week