Cholinergics- Nicotinics Flashcards
Nicotinics
Actions similar to nicotine, corresponds to actions of ACh released at autonomic ganglia, neuromuscular junction of skeletal muscle, and adrenal medulla
Nicotinic receptors
Ligand-dependent ion channels, allows Na and K flux down concentration gradient, depolarization, ionotropic
Types of nicotinic receptors
Nn- neuronal type, found in autonomic ganglia, blocked by ganglionic blockers
Nm- muscle typefound in neuromuscular junction, blocked by skeletal muscle relaxants
Nicotinic alkaloids
Both nicotine and lobeline are tertiary cholinomimetic alkaloids and well absorbed, excreted mostly by the kidneys, acidification of urine accelerates their clearance (weak bases)
Nicotine
Lipid-soluble, can be absorbed across the skin, indicated for assistance to smoking cessation
Lobeline
Plant derivative similar to nicotine, no clinical indication
Nicotinic choline esters
High affinity for nicotinic receptors, resistant to AChE, induces muscle paralysis during surgery by depolarizing blockade
Normal conditions
Agonists like ACh binds to nicotinic receptors and opens channels, AChE rapidly metabolize ACh, channels close
Depolarizing blockade
Succinylcholine (agonist) binds to nicotinic receptors and channels open, succinylcholine is resistant to metabolism, sticks around, causing channels to become unresponsive, prolonged presence causes channels to become less receptive and stay unresponsive
Nicotinic effects in CNS
Presynaptic nicotinic receptors regulate release of neurotransmitters (glutamate, serotonin, GABA, dopamine, norepinephrine), high concentration induces tremors, emesis, respiratory center stimulation, higher concentrations may cause convulsions and fatal coma
Clinical uses of nicotine
Direct-acting alkaloid, used for smoking cessation
Clinical uses of succinylcholine
Direct-acting choline ester, used for neuromuscular blockade during surgery, rapid sequence intubation
Side effects of nicotinics
Central stimulant- convulsions that may progress to coma and respiratory arrest
Skeletal muscle end plate depolarization- depolarization blockade and respiratory paralysis
Cardiovascular- hypertension and cardiac arrhythmias
Fatal dose of nicotine
Amount of nicotine in two regular cigarettes, most is destroyed by burning or escaping through second hand smoke
Function of ganglion blocking agents
Competitively block nicotinic receptors of parasympathetic and sympathetic autonomic ganglia
Ganglion-blocking agents
Tetraethylammonium (TEA)- short duration of action, Hexamethonium (C6)- prototypical agent used experimentally, Decamethonium (C10)- analogue of hexamethonium, Mecamylamine, Trimethaphan
Mechanism of action of ganglion-blocking agents
Nondepolarizing competitive antagonists, hexamethonium binds directly to nicotinic ion channel, trimetaphan blocks the nicotinic receptor, not the channel pore
Effects of ganglion-blocking agents on the CNS
Mecamylamine crosses the BBB, causes sedation, temor, choreiform movements, mental aberrations, discontinued in 2009
Effects of ganglion-blocking agents in the eye
Cycloplegia with loss of accommodation because ciliary muscle receives primarily parasympathetic innervation, parasympathetic tone dominates the pupil, blockade causes moderate pupil dilation
Cardiovascular effects of ganglion-blocking agents
Blood vessels only innervated by sympathetics, blockade normally decreases arteriolar and venous tone, heart normally under parasympathetic innervation, blockade causes moderate tachycardia
Effects of ganglion-blocking agents on GI tract
Parasympathetic normally predominates, blockade reduces secretion, inhibits motility, causes constipation
Genitourinary effects of ganglion-blocking agents
Blockade causes hesitancy in urination, may precipitate urinary retention in men with prostatic hyperplasia, sexual function impaired due to prevention of erection and ejaculation
Cholinesterase (ChE)
Terminates the action of ACh, located on the basement membrane of the synaptic cleft of cholinergic neurons
Structure of cholinesterases
Serine hydrolases, active site consists of: anionic site which binds choline group, esteratic site where acetyl group is transferred during catalytic hydrolysis- releasing choline
Cholinesterase inhibitors (ChEI)
Reduce choline metabolism and increase endogenous choline conentration- cholinomimetic
Classes of ChEI
Simple alcohols- quaternary ammonium group (edrophonium)
Carbamic acid esters of alcohol- quaternary or tertiary ammonium groups (neostigmine, physostigmine)
Organic derivatives of phosphoric acid- organophosphates (isoflurophate)
Short acting ChEI
Edrophonium, binds to anionic site of cholinesterase and forms hydrogen bond to prevent ACh binding, reversible
Intermediate acting ChEI
Neostigmine, pyridostigmine, physostigmine, carbamyl group binds to AChE, breaking the carbamyl enzyme group is slower than the acetyl group, reversible
Long acting ChEI
Echothiophate, other organophosphates, organic group is released upon binding, leaving phosphorus covalently bound in AChE
Organophosphates and aging
Covalent binding stable, aging occurs when there is a loss of an alkyl group (makes phosphorylated enzyme more stable), hydration still occurs, rate is slow and “irreversible”, new enzymes must be synthesized for activity
CNS effects of ChEI
High concentrations, lipid soluble ChEI causes generalized convulsions that can lead to coma and respiratory arrest
Effects of ChEI in the eye, respiratory tract, GI tract, urinary tract
Similar to direct-acting cholinomimetics- miosis, bronchoconstriction, urination, GI motility, secretion, defecation
Effects of ChEI on glands
Secretion in sweat, lacrimal, salivary, nasopharyngeal glands
Effects of ChEI in the heart
Parasympathetic effect predominates, moderate doses reduce heart rate
Effects of ChEI in vasculature
No parasympathetic innervation, sympathetic effect predominates, due to quaternary agents at autonomic ganglion and lipid soluble agents at central sympathetic centers
Net cardiovascular effect of ChEI
Moderate dose- modest bradycardia and increased vascular resistance, increased blood pressure
High dose- bradycardia and hypotension
Effects of low doses of ChEI at neuromuscular junction
Moderately prolong and intensity actions of ACh, increase strength of contraction especially in weakened muscles (myasthenia gravis)
Effects of high doses of ChEI at neuromuscular junction
Result in muscle fiber fibrillation, antidromic firing (backward axon conduction toward soma) resulting in fasciculations of entire motor unit, depolarizing neuromuscular blockade followed by nondepolarizing blockade
Myasthenia gravis
Autoimmune disorder where circulating antibodies block ACh action at the postsynaptic neuromuscular junction, causing fluctating muscle weakness and fatigue, symptoms are ptosis, diplopia, difficulty speaking and swallowing, extremity weakness
Mechanism of antibodies in myasthenia gravis
Cross-link receptors and stimulate receptor internalization and degradation, cause lysis of postsynaptic membrane, bind to and inhibit nicotinic receptors
Edrophonium
Short-acting ChEI, used in diagnosis of myasthenia gravis, nondepolarizing reversal of neuromuscular blockade, improves muscle strength for about 5 minutes, not used for long term treatment
Neostigmine
Intermediate-acting ChEI, nondepolarizing reversal of neuromuscular blockade, urinary retention, myasthenia gravis, additional direct nicotinic agonist activity
Pyridostigmine
Intermediate-acting ChEI, used for reversal of neuromuscular blockade, myasthenia gravis (drug of choice), prophylaxis for organophosphate poisoning, slower onset but longer duration of action than pyridostigmine
Physostigmine
Intermediate-acting ChEI, used for glaucoma, reversal of anticholinergic toxicity, crosses the BBB
Echotiophate
Long-acting ChEI, used for glaucoma, esotropia with accommodative compensation, long duration can lead to acquired cholinesterase deficiency and prolonged block from neuromuscular blocking drugs
ChEI side effects
Muscarinic side effects initially predominate, central side effects follow rapidly (cognitive disturbances, convulsions, coma), followed by peripheral nicotinic effects (depolarizing neuromuscular blockade)
Cholinergic poisoning
Severe cholinergic excess is medical emergency, caused by insecticides, wild mushrooms, chemical warfare (nerve gases- sarin, VX, soman), nicotinic and muscarinic effects can be life-threatening, no treatment for nicotinic poisoning
Treatment options for cholinergic poisoning- reverse muscarinic effects
Tertiary amine drug must be used to treat CNS effects as well as peripheral effects of organophosphate inhibitors, atropine
Treatment options for cholinergic poisoning- cholinesterase regenerator compounds
Contain substituted oximes, not recommended for reversal of inhibition by carbamate inhibitors, pralidoxime- ineffective for reversing central effects of organophosphate poisoning due to charged quaternary ammonium groups
Cholinesterase regenerator
Organophosphates cause phosphorylation of serine OH group at active site of cholinesterase, oxime group has high affinity for phosphorus atom and competes with serine OH of cholinesterase
Pralidoxime
Cholinesterase regenerator, can hydrolyze phosphorylated enzyme and regenerate cholinesterase if the organophosphorus-cholinesterase complex has not aged
Treatment options for cholinergic poisoning- pretreatment with reversible enzyme inhibitor
Prevents binding of irreversible organophosphate inhibitor, reserved for situations in which possible lethal poisoning is anticipated, simultaneous use of atropine required to control muscarinic excess
Mushroom poisoning
Rapid onset, IV atropine for muscarininc excess, A. muscarina ingestion can cause atropine poisoning
