Stigmata Gravis Cholinesterase Inhibitors

1.2 – “Stigmata Gravis”: Cholinesterase inhibitors (neo (neostigmine, stigmine, pyridostigmine, edrophonium, physostigmine, organophosphat organophosphates, es, galantamine, rivastigmine, donepez donepezil) il) • Acetylcholinesterase (AChE) hydrolyzes ACh in post synaptic cleft, decreasing its availability for signaling (dumpster full of acetyl-cola bottles; anti-establishment graffiti). • Indirect cholinomimetics reversibly or irreversibly bind AChE, blocking ACh degradation →↑ availability for signaling in synaptic cleft (“Acetyl-Cola” billboard visible indistinctly, or indirectly, in the distance; acetyl-cola bottles spill out of knocked over dumpster, suggesting ↑ACh availability in synaptic cleft). Most end in -stigma drug suffix (stigma graffiti). Effect is similar to that of cholinomimetics in eye, GI tract, respiratory tract, & urinary tract. Specifically: o Enhances effects of ACh at NMJ endplate by acting on nicotinic ACh receptors (brick wall looks like skeletal muscle, with electrical outlet). Results in increased contraction strength, used in treatment of myasthenia gravis (Gravis graffiti with a grave marker). ▪ Myasthenia gravis is an autoimmune disorder with production of antibodies against NMJ nicotinic receptors. Presents with progressive proximal weakness, ptosis, diplopia, difficulty swallowing. Cholinesterase inhibitors are used for symptomatic relief; immunosuppression is used for autoimmune disease. • Endogenous & exogenous tertiary amines can cross BBB. Synthetic quaternary amines class do not, because of charge. Drugs: Gene General ral • Pyridostigmine (volunteer with “Pride” jacket cleaning graffiti) o Used in long term treatment of myasthenia gravis o Quaternary amine (“Quarters only” sign on phone booth) • Neostigmine (neon sign) o Not used as commonly as pyridostigmine in treatment of MG. o Treats urinary retention d/t muscarinic activity (bladder hose) o Can be used to reverse nondepolarizing neuromuscular blockade o Quaternary amine (“Quarters only” sign on phone booth) • Edrophonium (phone both) o Very short action, ~5 minutes, allows use for tensilon test to determine whether exacerbation of MG symptoms is d/t overtreatment or undertreatment. MG overtreatment → ACh receptor overstimulation & refractory receptors = cholinergic crisis; looks similar to MG symptomatology. If signs & symptoms improve with edrophonium, suggest undertreatment (tense phone wire for ⊕ tensilon test) . (Phone booth in working order to remind of edrophonium reversing muscle weakness in undertreated. Busted up phone booth with slack wire suggests edrophonium fails to reverse muscle weakness = ⊖ test) o Quaternary amine (“Quarters only” sign on phone booth) • Physostigmine (phys-ed center) o Reverses atropine OD in the CNS by increasing ACh concentration at synapse to overcome competitive inhibition (Alice graffiti; phys ed teacher reprimanding atropine graffiti artist). Also used in cases of belladonna (deadly nightshade) or Jimson weed toxicity (flower in Alice’s hand, weeds in front of gym). o Crosses BBB, which can cause central cholinergic effects (“Your brain on drugs” poster). Toxicity remembered as “DUMBBELSS” (guy working out in gym, unable to lift weights) ▪ Diarrhea ▪ Urination ▪ Miosis/muscle weakness ▪ Bronchorrhea ▪ Bradycardia ▪ Emesis ▪ Lacrimation ▪ Salivation/sweating o Weak nAChR effects, such that toxicity includes flaccid paralysis (limp kid) Drugs: NMJ bblockade lockade • NMJ blockade used in, e.g., surgery. • Nondepolarizing agents o Curare compounds include tubocurarine, pancuronium, cisatracurium ▪ Inhibit nAChRs at NMJ endplate (CURARE brand crayons stuck in electrical outlet) • Depolarizing agents o Succinylcholine (“Sucks” graffiti) ▪ Overstimulate nAChRs at NMJ endplate, causing a prolong refractory period (Volunteer is getting a shock; he is overstimulated). ▪ Two phase block • Phase 1 of depolarizing blockade is irreversible (phase 1 clean-up crew getting shocked). Na channels surrounding motor end plate are inactivated & cannot reopen until the end plate is repolarized; results in flaccid paralysis. AChE inhibitors have no reversal effect in this phase. • Phase 2 With continued administration, nAChR become desensitized and gradual repolarization occurs. This is similar to a non-depolarizing blockade, & AChE inhibitors may help reverse. ▪ Hydrolyzed in the cytoplasm by pseudocholinesterase, such that typically only 10% of administered succinylcholine actually reaches NMJ. • In patients with a pseudocholinesterase deficiency, an autosomal recessive disorder caused by polymorphism in the BCHE gene, use of succinylcholine as an anesthetic can cause prolonged paralysis of respiratory musculature, and prolonged post-op apnea. Little risk of harm to patient if mechanical ventilation is maintained. Otherwise, this is a benign condition. ▪ Adverse effects: • Malignant hyperthermia in genetically susceptible patients, especially with halothane • Severe hyperkalemia in patients with burns, myopathies, crush injuries, & denervation. Occurs because the nAChR is a nonselective cation channel, and opening allows both Na influx & K efflux. Seen in these specific patient populations d/t upregulation of muscular nAChRs. • Bradycardia from PNS stimulation or tachycardia d/t SNS effects Alzheimer’s tre treatments atments • Galantamine (Alzheimer's gala), rivastigmine (release stigma), donepezil (done with puzzle) o All cross BBB o Benefits modest. Must be balanced against risk of major adverse effects d/t ↑ AChE activity. AChE inhibito inhibitorr OD • Seen with exposure to organophosphates, used commonly in insecticides, like parathion, malathion, echothiopate, as well as nerve agents & herbicides (dude spraying “THIOL” herbicide outside gym) Can cause thiosulfate toxicity, & major cause of acute cholinergic toxicity (green fumes causing weightlifter’s weakness). • Toxicity must be recognized immediately. Organophosphates bind covalently to AChE; left too long, aging of organophosphatecholinesterase complex leads to irreversible binding (older pest control man has irreversibly damaged AChE dumpster). o DUMBBELSS toxicity • Pralidoxime reverses peripheral toxicity (toxic dumpster with lid open) o increasing hydrolysis of covalent bond → regenerates AChE at peripheral muscarinic & nicotinic receptors, reversing cholinergic toxicity including flaccid paralysis (new AChE dumpsters). o Does not cross BBB, so will not reverse CNS muscarinic effects. • Atropine reverses muscarinic toxicity (Alice’s head on toxic waste dumpster) o Crosses CNS. Reverses muscarinic toxicity in both peripheral & central nervous systems.