Cholinergic Pharmacology Pt 2 Flashcards
Cholinergic agonists
can interact directly with nicotinic or muscarinic receptors or both (agonists)
parasympathomimetics
drugs producing only muscarinic effects
Direct acting agonists
- Choline esters
- Naturally occurring alkaloids
- Ganglionic stimulating agents
Carbachol
- nicotinic and muscarinic agonist
- choline ester
- longer lasting than but has both nicotinic and musarinc effects
methacholine
- muscarinic agonist
- choline ester
- mostly muscarinic
- decrease nicotinic effect
- mostly cardiac
Choline esters
- Carbachol, Methacholine, Bethanechol
- somewhat selective, resistant to action of cholinesterase (hydrolysis) competed to Ach so longer duration fo action
Bethanechol
- choline ester
- muscarinic specific
- mostly GI and bladder
Naturally occurring alkaloids
- muscarinic agonists
- muscarine and pilocarpine
Ganglionic stimulating agents
- nicotinic agonists
- Nicotine
- Lobeline
Ganglionic stimulating agents effects
- no therapeutic usage
- produce generalized stimulation of autonomic ganglia and mixed symp and parasympathetic responses
- blood pressure increase bc vasoconstriction bc symp ganglia stimuli and release epinephrine from adrenal medulla
- gut motility increase or decrease
- secretion salvia, bronchial mucus, and sweat increased
Ganglionic stimulating agents effects at v high doses
- at v high doses cause blockade bc depolarization block, reflecting inactivation sodium channels and desensitization nicotinic receptors
Anticholinergic/ cholinergic antagonists
muscarinic antagonists
muscrinic antagonists
Atropine, scopolamine, homatropine
Muscarinic antagonists fx
- competitive inhibitors at parasympathetic neuroeffect junctions
- can block nicotinic sites at V high concentrations
muscarinic antagonisti are derived from
- alkaloids derived from deadly nightshade, jimosn weed, henbane or synthetic analogs of these products
- these are toxicologically important
Pharmacological actions of muscarinic antagonists heart
- tachycardia deepening on vagal tone (horse + dog)
Pharmacological actions of muscarinic antagonists blood vessels
- not innervated (most muscarinc receptor in blood vessels not innervated), little effect
- block vasodilation induced by choline esters
Pharmacological actions of muscarinic antagonists GI and urinary tracts
decrease tone, motility, and secretions
Pharmacological actions of muscarinic antagonists respiratory
increase luminal diameter, decrease bronchial secretions
- low doses stimulate respiration high doses inhibit
Pharmacological actions of muscarinic antagonists eye
relax sphincter muscle of iris and colliery muscles of sense -> mydriasis and cycloplegia (loss ability to accommodate near vision)
-increased intraocular pressure bc canals of Schelmm blocked
muscarinic antagonists and glaucoma
contraindicated
Pharmacological actions of muscarinic antagonists sweating
impaired (sympathetic; horse is excetption bc horse is noradernergic sweater)
Pharmacological actions of muscarinic antagonists salivation
reduced -> dry mouth
Pharmacological actions of muscarinic antagonists CNS
- moderate doses stimulate medullary and higher centers
- higher doses -> restlessness, disorientation, delirium, hyperthermia (bc of effect on medulla and higher centers)
- even higher doses depression, coma, death bc medullary paralysis
Ganglionic blocking agents
- nicotinic antagonists (competirei antagonists)
- non-depolarizing
- block symp and parasympathetic ganglia -> loss tone to organ
- not used in vet med
non-depolarizing ganglionic blockers
- hexamethonium (H6) and trimethaphan
nonâ-depolarizaing ganglionic blockers fx
competitively compete with ACh for nicotinic receptor sites at ganglia and adrenal medulla
net response organ system depends on predominant tone
parasympathetic predominant tone
USE GBH (Use great big hug)
- Urinary bladder
- Salivary gland
- Eye (Iris and ciliary muscle)
- GI
- Bronchioles
- Heart
sympathetic predominant tone
AVS
- Arterioles
- Veins
- Sweat glands
types ganglionic blocking agensts
- non-depolarizing ganglionic blockers
- depolarizing ganglionic blockers
depolarizing ganglionic blockers
- Nicotine and Lobeline
depolarizing ganglion blockers mechanism action
- cause initial sustained depolarization followed by receptor blockade bc inactivation Na+ channels and desensitized receptor
nicotine
- depolarizing ganglionic blocker
- also functions as depolarizing blocker at NMJ
- Has been used as incedicide and wildlife capture drug
depolarization ganglion blockers poisining
characterized by initial stimulation of ganglia followed by blockade, death caused by antagonist effects (at respiratory muscle NMJs)
prejunctional anticholinergics
- antagonists
- don’t discriminate between muscarinic and nicotinic synapses/ junctions
- Hemicholinium
- Botulinus Toxin
- Opioids
- Local Anestethics
hemicholinium
- HC-3
- blocks choline transport system, little to no effect on choline acetyltransferase
- inhibition choline uptake -> limit synthesis ACh and decrease amount transmitter available for release
Botulinus toxin
- prevents release vesicular ACh at all cholinergic fibers
- peripheral respiratory paralysis -> death
Opioids
- stimulate enkephalin receptors in gut -> inhibition of release of acetylcholine
Local Anestetics
- block sodium channels and inhibit generation and propagation of action potentials
Indirectly acting agonists
- cholinesterase inhibitors
- act on acetylcholinesterase and butyrycholinesterase
3 types:
1. Short acting/ reversible inhibitors
2. Carbamylating Esters
3. Phosphorylating Agents
Acetylcholinesterase (AChE(
- true or specific ChE
- normal metabolism for termination of cholinergic transmission
- AChE= generally membrane associated and found in nerve terminals in PNS, NMJ, on erythrocytes, and in gray matter of CNS
Butyrylcholinesterase (BuChE)
- aka serum or pseudo cholinesterase
- generally soluble and found in blood serum and in white matter of CNS
Short acting reversible cholinesterase inhibitors
- indirectly acting agonists
- Enrophonium (Tension)
Enrophonium
-aka Tension
the following also true for general short acting reversible cholinesterase inhibitors?:
- shortest acting AntiChE
- Combines with AChE primarily at cation binding site forming rapidly reversible enzyme-inhibitor complex
Enrophonium as diagnostic tool
- inhibit Ache get more Ach; if -> more weakness issue is too much Ach as opposed to not enough receptors
Carbamylating esters
- type indirectly acting agonist
- Physostigmine (Eserine)
- Neostigmine (prostigmine)
- Pyridostigmine
- all reversibly inhibit ChE for few hours
Phosphorylating agents
- aka organophosphates
- essentially irreversibly inhibit ChE and new enzyme must be synthesized for recovery to occur
- importantly clinically for toxicity and poisoning
Organophosphates characteristics
- v lipid soluble (except echothiophate)
- high vapor pressures (volatile)
- extremely toxic bc of above characteristics
types organophosphates
- phosphates and phosphothionates
phosphates examples
- DFP
- Paraoxon
- Dichlorvos
- Echothiophate
Phosphothionates
- Parathion
- Malathion
- these must be converted to phosphonates via P450 oxidation enzyme in liver to be active
Organophosphates used for
insecticides, pesticides, nerve gas
signs cholinesterase inhibitor poisoinig
DUMBBELSS
D- D+ U- urination M- miosis B- bronchospasm B- bradycardia E- Neuromuscular excitation L- lacrimation S- sweating S- salivation
Pharmacological effects organophosphate poisoning muscarinic
- salivation
- miosis
- V+
- defication
- hyper motility GI tract
- urination
- bradycardia
- hypotension
- severe bronchoconstriction
- excess bronchial secretions
Pharmacological effects organophosphate poisoning nicotinic effects
- NMJ: skeletal muscle fasciculations, twitching… patalysis
- ganglia- not observed often, sympathetic usually predominates
Pharmacological effects organophosphate poisoning CNS
- ataxia, confusion
Pharmacological effects organophosphate poisoning cause of death
usually respiratory failure but bronchoconstriction and convulsions (CNS) can be life threatening too
Treatment of organophosphate poisoning
Atropine
Pralidoxime
Atropine
- blocks muscarinic effects overwhelming the system
- Give IV slowly
Pralidoxime
- aka 2-Pam aka protopam, obidoxime, or diacetyl monoxime
- Give IV prior to “aging” (phosphorylation)
- charged so will not cross blood brain barrier and will not reverse CNS effects
- useful for nerve agent poising like nerve gas
Mechanism of action organophosphates steps
- Inhibition (phosphorylation)
- Reactivation (dephospho rylation)
- Aging
- Regeneration/ Recovery
Inhibition (phosphorylation)
OP reacts covalently w/ active site AChE
Reactivation (dephospho rylation)
spontaneous reactivation can occur but is V slow; 2Pam can reactive enzyme prior to aging
Aging
loss of alkyl group, enzyme irreversibly inihibited and v resistant to regneration with 2-PAM
Regeneration/ Recovery
if enzyme not reactivated with 2-PAM new AChE must be synthesized only small fraction AChE need to be resynthesizes for full functional recovery
Acetylcholine esterase sites and 2-PAM
- anionic site and serine molecule= catalytic site where hydrolysis cleavage event occurs; carbonyl transferred to serine -> stable intermediate that stays bound for longer, site regenerated can accept acetyl choline molecule organophosphates have phosphate bind ot serine -> permanent inactivation of enzyme, pralidoxime (2-PAM) gets phosphate off serine and reactivates enzyme
