Prelim Chapter 4 CHOLINERGIC AGONISTS Flashcards
•act on receptors (muscarinic or nicotinic) that are activated by acetylcholine (ACh)
Cholinergic Agonists
•drugs that mimic the actions of acetylcholine
Cholinomimetic Drugs
•neurotransmitter on the following sites:
– preganglionic fibers terminating in the adrenal medulla
– autonomic ganglia (both sympathetic & parasympathetic)
– postganglionic fibers of the parasympathetic division
– postganglionic sympathetic divison of sweat glands
– cholinergic neurons that innervate the muscles of the somatic system
Acetylcholine (ACh)
Neurotransmission at Cholinergic Neurons
•Synthesis
•Storage
•Release
•Binding of ACh to a receptor
•Degregadation of the neurotransmitter in the synaptic cleft
•Recycling of choline and acetate
…
•named after the alkaloid muscarine that mimics the effects of acetylcholine
•belongs to the class of G protein coupled receptors (metabotropic)
•5 subtypes but M1, M2 and M3 have been functionally characterized
Muscarinic Receptor
•drugs that bind in the muscarinic receptors and elicit pharmacological actions
Muscarinic Agonists
•ganglion and skeletal muscle receptors stimulated by low concentration of nicotine
– NM - found in the neuromuscular junctions
– NN - found in the CNS, adrenal medulla, autonomic ganglia
Nicotinic Receptors
- found in the neuromuscular junctions
NM
- found in the CNS, adrenal medulla, autonomic ganglia
NN
Parasympathetic Effects
•D - Diarrhea/ Diaphoresis
•U - Urination
•M - Miosis
•B - Bradycardia/ Bronchoconstriction
•E - Emesis
•L - Lacrimation
•S - Salivation
…
Dumbels means
•D - Diarrhea/ Diaphoresis
•U - Urination
•M - Miosis
•B - Bradycardia/ Bronchoconstriction
•E - Emesis
•L - Lacrimation
•S - Salivation
Organ Effects of Direct-Acting Cholinoceptor Drugs
Organ-Response
Eye (Sphincter muscle of iris)- Contraction (Miosis)
(Ciliary Muscle)-Contraction for near vision
Heart-Negative chronotropy, inotropy and dromotropy
Blood Vessels-Dilation; Constriction (high doses)
Lungs-Bronchoconstriction; Bronchial glands stimulation
GI Tract-Increase motility, Secretion stimulation
Urinary Bladder-Contraction; Relaxation of sphincters
Glands-(sweat, salivary, lacrimal, nasopharyngeal)
MOA of Cholinomimetic Drugs
•Direct-acting Cholinomimetic Drugs - bind to and activate muscarinic or nicotinic receptors
•Indirect-acting Drugs - inhibits acetylcholinesterase (AChE), which hydrolyzes acetylcholine to choline and acetic acid
…
- bind to and activate muscarinic or nicotinic receptors
Direct-acting Cholinomimetic Drugs
inhibits acetylcholinesterase (AChE), which hydrolyzes acetylcholine to choline and acetic acid
Indirect-acting Drugs
•a quaternary ammonium compound that cannot penetrate membranes
•Effects:
–decrease in heart rate and cardiac output
– decrease in blood pressure
– DUMBELS
ACETYLCHOLINE
•Urecholine®
•Actions: Causes increased secretion, smooth muscle contraction (except vascular smooth muscle - relaxes), and changes in heart rate
CA: Postoperative and neurogenic ileus and urinary retention
•S/E: Generalized cholinergic stimulation (sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, bronchospasm
•Antidote: Atropine
BETANECHOL
•Carboptic®, Miostat®, Carbastat®
•Actions: similar to betanechol
•CA: used topically almost exclusively for glaucoma
Carbachol
Endogenous Choline Esters
ACETYLCHOLINE
BETANECHOL
Carbachol
Direct-Acting Muscarinic Alkaloids or Synthetics
PILOCARPINE
Cevimeline
•Isopto Carpine®
•Actions: effects are similar to betanechol; produces rapid miosis
•CA: Glaucoma, Sjogren’s Syndrome
S/E: blurred vision, night blindness, brow ache, exaggeration of various parasympathetic actions
•Antidote: Atropine
PILOCARPINE
•Evoxac®
•Synthetic
•Similar to pilocarpine
Cevimeline
Direct-Acting Nicotinic Agonists
Nicotine
•Activates autonomic postganglionic neurons and skeletal muscle neuromuscular end plates
•CA: medical use in smoking cessation
•S/E: N & V, Increased BP, Long term GI and CV risk factor
•Interaction: Additive to CNS stimulant
Nicotine
INDIRECT-ACTING CHOLINOMIMETICS
3 Chemical Groups of Cholinesterase Inhibitors
•Simple alcohols bearing a quaternary ammonium group (eg. Edrophonium)
•Carbamic acid esters of alcohols having quaternary or tertiary ammonium groups (carbamates, eg. Neostigmine)
•Organic derivatives of phosphoric acid (organophosphates)
ORGANOPHOSPHATES
•Echothiophate - has a clinical value
•Soman - an extremely potent “nerve gas”
•Parathion & Malathion - (sulfur-containing phosphate) prodrugs that are converted to phosphate derivatives in animals and plants and used as insecticide
MOA
•Increase the concentration of endogenous acetylcholine at cholinoreceptors by inhibiting acetylcholinesterase enzyme
- “irreversible” cholinesterase inhibitor
Organophosphates
- “reversible” cholinesterase inhibitor
Edrophonium and Carbamates
The EYE
•Glaucoma - a disease characterized by increased intraocular pressure
•Acute angle-closure glaucoma - a medical emergency that is frequently treated initially with drugs but usually requires surgery for permanent correction
•Accomodative esotropia (strabismus caused by hypermetropic accomodative error)
The EYE
- a disease characterized by increased intraocular pressure
•Glaucoma
- a medical emergency that is frequently treated initially with drugs but usually requires surgery for permanent correction
•Acute angle-closure glaucoma
•(strabismus caused by hypermetropic accomodative error
Accomodative esotropia
GI and URINARY TRACTS
•Postoperative atony - paralysis of the stomach or bowel following surgical manipulation
•Neurogenic bladder
…
•Myasthenia gravis
•Curare-induced neuromuscular paralysis..
Neuromuscular Junction
In HEART
•———- was used to treat supraventricular tachyarrhythmias
Edrophonium
In Central Nervous System
•———-(Cognex) - drug with anticholinesterase and other cholinomimetic actions used for the treatment of mild to moderate Alzheimer’s disease
TACRINE
Donepezil - Aricept
•Galantamine - Reminyl
•Rivastigmine - Exelon
…
Short-Acting Cholinesterase Inhibitor
EDROPHONIUM
Myasthenia Gravis
AMBENONIUM
•Tensilon®
•MOA: Binds briefly to active site of AChE and prevents access of ACh
•Effects: Amplifies all actions of ACh (increases parasympathetic activity and somatic neuromuscular transmission)
CA: Diagnosis and acute treatment of myasthenia gravis
•Toxicity: Parasympathomimetic excess
EDROPHONIUM
•an autoimmune disease affecting skeletal muscle neuromuscular junctions
•S/Sx: ptosis, diplopia, difficulty in swallowing and extremity weakness
ium given IV after baseline muscle strength is measured
•if no reaction occurs after 45 sec, an additional 8 mg may be injected
•Positive result = the patient has improvement in muscle strength that lasts for 5 minutes
Myasthenia Gravis
•Mytelase®
AMBENONIUM
Intermediate-Acting Cholinesterase Inhibitors
NEOSTIGMINE
PYRIDOSTIGMINE
PHYSOSTIGMINE
RIVASTIGMINE
•Prostigmin®
•MOA: forms covalent bond with AChE, but hydrolyzed and released
•Effect: like Edrophonium but longer-acting
•CA: Myasthenia gravis
NEOSTIGMINE
•Mestinon®, Regonol®
•Like neostigmine, but longer-acting
•also used in myasthenia gravis
PYRIDOSTIGMINE
•Eserine®
•like neostigmine
•a natural alkaloid tertiary amine
•enters CNS
PHYSOSTIGMINE
•Exelon®
RIVASTIGMINE
Long-Acting Cholinesterase Inhibitor
Echothiophate
Malathion
Parathion
Sarin
TOXICITY
•Antidote: ATROPINE
•Organophosphate Posioning: ATROPINE, DIAZEPAM, PRALIDOXIME
•MOA: like neostigmine, but released more slowly
•Obsolete - was used in glaucoma
Echothiophate
•insecticide
•relatively safe for mammals and birds because metabolized by other enzymes to inactive products
•some medical use as ectoparasiticide
Malathion
•Insecticide
•Dangerous for all animals
•Toxicity is important because of agricultural use and exposure of farm workers
Parathion
•”Nerve gas”
•used exclusively in warfare and terrorism
Sarin
