CHOLINOMIMETICS &CHOLINOESTERASE INHIBITING DRUGS

Recepror types:

#M1 => nerves/ 7 transmembrane segments; Gq protein linked/ IP3, DAG cascade: increased gastric acid secretion & CNS activation

#M2=>generally cardiac type: heart, nerves, smooth mm./ 7 transmembrane segments; Gi protein linked/ inhibition of cAMP, activation of K+ channels/ increased bronchi secretion, ganglia secretion, negative inotropic ( decrease in heart contactility), chronotropic ( decrease in HR)

#M3=>glands, smooth mm, endothelium/ 7 transmembrane segments; Gq protein linked/ IP3, DAG cascade

#M4=> CNS & GI tract/ 7 transmmebrane segments; Gi protein linked/ inhibition of cAMP production

#M5=> CNS/ 7 transmembrane segments; Gq protein linked/ IP3, DAG cascade

*NM=> muscle type, end plate receptor; skeletal muscle neuromuscular junction/ pentamer/ Na+, K+ dep. ion channel

*NN=> neuronal type, ganglion receptor; CNS, postganglionic cell body, dendrites/ pentamer/ Na+, K+ dep. ion channel

1) DIRECT AGONISTS

#MUSCARINIC

a) choline esters:

*BETHANECHOL: activates M1 through M3 receptors in all peripheral tissues; causes increased secretion, smooth mm. contaction ( exception! vascular smooth mm. relax), changes in heart rate. Used in postoperative ileus ( GI atonia), urinary retention. Doesn't eneter CNS, can cause excessive parasymp. effects ( esp. bronchospasm in asthmatics) as toxic effect, acts 0.5-2 hrs , resistant ChEsterase, rapidly hydrolyzed

b) alkaloids

*PILOCARPINE: like bethanechol, partial agonist. Used in galucoma (only topically as gutt.ophth.) and Sjoergen syndrome ( per os), acts 0.5-2 hrs, not ester, good lipid solubility

*CEVIMELINE: selective M3-selective agonist; similar to pilocarpine, for galucoma & Sjoergen

#MUSCARINIC& NICOTINIC

*CARBACHOL: similar to bethanechol ( ChEsterase resistant) , used almost exclusively for glaucoma, acts 0.5-2 hrs

#NICOTINIC

*SUCCINYLCHOLINE: moderately selective for neuromoscular end plate ( NM receptors), elicits muscle relaxation ( IV or IM injection); highly polar, duration 5-10 min., toxic effects may include: initial muscle spasms, postoperative pain, may cause increase in intraocular pressure ( GLAUCOMA IS CONTRADICATION!)

*VARENICLINE: acts similar to nicotine but longer, used in smoking cessation, partial agonist of N receptors, high lipid solubility, acts 12-24 h

*NICOTINE: agonist at both NN and NM receptor, high lipid solubility; activates postganglionic neurons ( both symp. & parasymp.) and skeletal mm. nauromuscular end plates, enter CNS and activates NN receptors. Used in smoking cessation, nonmedical use in smoking and in insecticides. Can cause increased GI motility, nausea, vomiting, diarrhea, increased BP, seizures ( in high doses), acts 1-6 hrs

2) INDIRECT AGONISTS

a) reversible

# 3rd order compounds (coss blood-brain barrier, lipid soluble, central nervous system action)

*PHYSOSTIGMINE: carbamate, tertiary amine, good lipid solubility, orally active inhibitor of cholinesterase, amplifier of endogenous released ACh, natural alkaloid tertiary amine , lipid soluble, duration 0.5-2-4h, used in severe atropine poisoning, ocassionally used in acute galucoma ( topically)

*RIVASTIGMINE: cholinesterase inhibitor, lipid soluble, enters CNS, half life 1.5-70 h; used in Alzheimer's disease

*DONEPEZIL: cholinesterase inhibitor, lipid soluble, enters CNS, half life 1.5-70, used id Alzheimer's disease

*GALANTAMINE ( as above)

*TACRINE (as above)

#4th order compounds ( poorly cros blood-brain barrier, peripheral action, poor lipid solubility)

*EDROPHONIUM: alcohol; quaternary amine, poor lipid solubility, nor orally active, binds briefly to AChEsterase and prevents access of ACh, acts 5-15 min. ; amplifies all actions of ACh- increases parasymp. activity and somatic nauromuscular transmission, used in diagnosis and acute treatment of Myesthenia Gravis, ileus, arrhythmias, used parenterally, quaternary amine, doses do not enter CNS; ADDITIVE WITH PARASYMPATHOMIMETICS!

*NEOSTIGMINE: carbamate, quaternary amine, poor lipid solubility, orally active, forms covalent bond with AChEsterase but hydrolyzed and released, acts up to 0.5-2h (longer than edrophonium), used in myesthenia gravis, postoperative and neurogenic ileus, urinary retention, CAN STOP EFFECTS OF CURRARE-LIKE DRUGS!!

*PYRIDOSTIGMINE: carbamate, acts 3-6 hrs ( longer than endrophonium), binds to AChEsterase, ; used in myesthenia gravis

*AMBENONIUM: 10 times stronger than neostigmine, acts 4-8 hrs, used in meusthenia gravis

b) irreversible

* ECHOTHIOPATE: organophosphate, moderate lipid solubility, forms covalent bond with AChEsterase bur released much more slowly, acts much longer than neostimine ( >4, ca. 100 hrs) was used in galucoma, can cause brow ache, uveitis, blurred vision

*MALATHION: insecticide ( safe for mammals)

*PARATHION: insecticide ( dangerous for all animals) , organophosphate, high lipid solubility, duration 7-30 days

*SARIN: nerve gas used in warfare and terrorism

Toxicity:

a) muscarinic: exagerated parasymp. activity; STOPPED BY ATROPINE

b)nicotinic: respiratory depression/ paralysis, arrhythmia, convulsions; atropine cannot be used as an antidote! treated by DRUGS regenerating active cholinesterase (OBIDOXIME, PRALIDOXIME) or STOPPED BY DIAZEPAM