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Cloned from: Pharmacology exam 2

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Acetylcholine (miochol)
  • only high IV doses result in short term detectable effects.  rapidly hydrolyzed by AChE
  • Indications: ocular surgery, directly into ant chamber - reduce postop ↑ IOP and produce miosis.  Lasts 20min
  • used in sweat spot test for ANS neuropathy in DM - subderm injec w/ iodide - black spots
Methacholine (provocholine)
  • last longer than ACh, better resits AChE
  • inhale nebulized soln - provoke bronchoconstriction in dx of bronchial airway hypersens
Carbachol (miostat)
  • Nicotinic activity (unmasked with atropine - a muscarinic blocker).  ↑ activity at ganglia, sk m. and adrenal medulla
  • Indications: intracameral instillation for miosis in ocular surg, reduce postop rise in IO P.  Drops reduce P in glaucoma, ocular hypertension.
  • SE: systemically produces CV/GI issues.  Limited to ophthalmic applications.
Bethanechol (urecholine)
  • no nicotinic activity
  • inc GI tone & motility
  • promotes bladder emptying in acute postop/postpartum nonobstructive urinary retention and in hypotonic, myotonic and neurogenic bladder.
  • Orally or SubQ injection
  • **only one admin systemically, most likely to produce systemic SE**
naturally occuring cholinomimetic agents - well absorbed
  • Muscarine
  • Pilocarpine
  • Nicotine
  • Chantix(other)
  • Muscarine
  • from Amanita muscaria
  • Cholinomimetic
  • Pilocarpine
  • Parasympathomimetic (muscarinic effects of ACh)
  • 3° amine, crosses BBB
  • longer acting than esters, less potent
  • most active on eye, sweat glands
  • eye: rapid miosis & accommodation in 10-20 min, lasts 4-8hr
  • tx open angle glaucoma: incr outflow of aq humor, reduces IOP - peak in 75 min for 4-14hr
  • CI if IOP > 45mmHg
  • reverse sympathomimetic mydriatics in eye exams
  • overcome mydriatic actions of atropine: used alternately to break up iris/lens adehsions
  • orally: incr saliva - used for xerostomia from radiation
  • SE: myopia, blurry, ciliary body spasm.  systemically: sweat, XS saliva, CV: sinus tachy, htn.
  • overdose: bradycardia, AV block
  • Nicotine
  • specific for nicotinic r's in autonomic ganglia, skeletal m. and CNS
  • can activate and inhibit nic ACh r's (activate after binding, become desensitized and mimics blockade → flaccid paralysis
  • acute: ↑ HR, BP via sympathetic ganglia stim, stim of epi secretion at adrenal medulla
  • ↑ GI tone & motility (via parasymp ganglia)
  • **smoking cessation agent**
  • toxicity: cholinergic N/V/D/dizzy, weak, ↑HR
  • chantix
  • partial agonist at neuronal nicotinic receptors
  • stim receptors in brain, simultaneously blocks actions of nicotine
  • black box: changes in behavior, hostility, agitation, depressed, suicidal
Indirect cholinergic agents
  • inhibit AChE, increase duration of action of ACh.
  • butyrylcholinesterase also does the same - in plasma, also inhib but not clinically relevant.
  • nicotinic agonists at NMJ
  • can be toxic due to wide distrib in body
  • therapeutic apps: alzheimer's, myasthenia gravis, glaucoma
Chemical groups used as Indirect cholinergic agents
  • Simple alcohols: 4° ammonium group (reversible)
  • Carbamic acid esters of alcohols, 4° ammonium group (reversible)
  • Organic deriv's of phosphoric acid (organophosphate) (irrreversible)
Lipid sol affects absorp: perm charged amonium - low lipid sol, less CNS penetration.  No perm charge means higher lipid solubility, readily absorbed everywhere, even skin!
Simple alcohols as indirect cholinergic agents
Inhibit binding of ACh for short periods (5-15min) by binding to enzymes via weak interactions.
ex: edrophonium
Carbamic acid esters as indirect cholinergic agents
Inhibit enzymes for longer period: 30m-6hr.
ex: neostigmine
Organophosphates as indirect cholinergic agents
Irreversible (for the most part).
Form covalent bond with enzyme - phosphorylation of serine residue in AS of enzyme.
Inhibits enzyme for hundreds of hours.
Further stabilized with aging (permanent inactivation)
PAM used before againg will displace the organophosphate.
PAM (Pralidoxime)
strong nucleophile used before againg to displace organophosphates and restore enzyme activity.
aka "cholinesterase regenerator" to treat organophosphate poisoning.
Organ efects of AChEI's
  • CNS
  • low [lipophilic agents] ↑ activity on EEG, ↑ alertness
  • high conc causes generalized convulsions, coma, respiratory failure
Organ efects of AChEI's
  • Eye, RT, GIT, GUT
  • all parasympathetically innervated
  • effects are similar to direct acting cholinomimetics
Organ efects of AChEI's
  • CVS
  • AChEI's cause increase in ACh in ganglia, postgang cells, CNS - all regulate CVS
  • predom: ↓HR, ↓conduc V, ↓F of contrac,  = results in ↓CO
  • since cholinerg innerv of vascular sm. m is minimal, there is min effect on vsm.
  • activation of symp gang, adrenal medulla would increase vasc R, at toxic doses can lead to tachycardia
  • net effect: ↓HR & CO. large doses result in brady/tachycardia and hypotension
Organ efects of AChEI's
  • NMJ
  • low dose: ↑endogenous ACh at nmj → ↑m contraction strength.
  • beneficial for myasthenia gravis or exposure to curare (NM block)
  • high conc: fibrillations, fasciculations of entire motor unit
  • toxic doses: depolarizing NM blockade, nondepolarizing blockade like succinylcholine.
Reversible anticholinesterases
  • Edrophonium
  • Physostigmine salicylate
  • Neostigmine
  • Donepezil
  • Tacrine
  • Galantamine
  • Pyridostigmine
  • Ambenonium
  • Demecarium
  • Carbaryl
Irreversible Anticholinesterases
  • Echothiophate
  • Malathion & Parathion
  • Nerve agents - Sarin, soman, tabun, VX
Reversible anticholinesterases
  • Edrophonium (tensilon)
  • short acting (5-15m) - too short for therapeutic use, but ideal for Dx of Myasthenia gravis to eval efficacy of myasthenia therapies
  • used to asses efficacy of LT anticholinesterase therapy in MG - sm amount of edro resulting in increased m strength indicates dosage is inadequate.  If dosage is adequate, pt will experience an increased muscle weakness due to depolarizing blockade of nicotinic receptors
Myasthenia Gravis diagnostic test
  • admin 2mg of Edrophonium IV, then 8mg.
  • + result means transient increase in muscle strength without lingual fasciculation (if pt has myasthenia)
  • an increase in m. weakness would inc onset of cholinergic crisis (overactivation!) - must treat with atropine to block muscarinic receptor activation
  • edrophonium+atropine can avoid this over activation
  • decreased m strength can also be d/t depolarizing blockade of nicotinic receptors  in presence of nicotinic agonist
Myasthenia gravis: causes
  • 90% of mg pts have an AI disorder that reduces AChRs on NMJ, reversible anticholinesterases would alleviate some muscle weakness
  • on the 10% with a congenital defect in receptor (with reduced ligand binding capacity), edrophonium doesn't improve myasthenia
Reversible anticholinesterases
  • Physostigmine salicylate (antilirium)
  • A carbamate, lasts 30m-6hr
  • x BBB
  • direct agonist at nicotinic NMJ r's
  • ophthalmic soln: miosis, accommodation, ↓ IOP lasting 2 hr (pilocarpine is more effective)
  • ↑ intestinal/bladder motility, used in nonobstructive paralytic ileus or post op atony of bladder
Reversible anticholinesterases
  • Neostigmine (prostigmin)
  • Synthetic carbamate, 4° ammonium, .5-2hr, no CNS entry
  • for myasthenia gravis, alleviate post op urinary retention, for paralytic ileus, after anesthesia to reverse NM blockade
  • also used to ↓IOP in glaucoma, or after eye surgery
  • SE if over stim:salivation, flushing, N/V/D, abd cramps, hypotension, bradycardia, bronchospasm
Reversible anticholinesterases
  • Donepezil (Aricept)
  • first piperidine reversible AChEI
  • hydrophobic, high AChE affinity, low butyrylcholinesterase affinity, long duration of action
  • symptomatic management of mild/severe Alzheimer's
  • Only works if there are available cholinergic neurons, so as the disease progresses, it works less.
  • doesn't prevent or inhibit progression of AD
Alzheimer's disease
Lesions from forebrain to CC and hippocampus involved in memory - cholinergic fibers modulate glutamate release, so inhibition of cholinesterases increases available ACh to help restore its modulatory function.  Must be intact cholinergic neurons, so AChEI therapy is short lived.
Reversible anticholinesterases
  • Tacrine (cognex)
  • 1st approved for improving cognitive function in AD
  • increases cholinergic activity in nuclei of forebrain
  • must monitor liver function (hepatocellular injury may be a SE)
  • donepezil doesnt have same hepatotoxicity
  • **significant cholinergic SE's**
Reversible anticholinesterases
  • Galantamine (reminyl)
  • Derived from daffodils for mild to moderate alzheimer's
  • no hepatotoxicity
Reversible anticholinesterases
  • Pyridostigmine (mestinon)
  • neostigmine analog with longer duration (3-6hr)
  • used for myasthenia gravis
Reversible anticholinesterases
  • Ambenonium (mytelase)
  • 4° ammonium, no CNS effects
  • for myasthenia gravis
  • duraction of 4-8hrs
Reversible anticholinesterases
  • Demecarium (humorsol)
  • 4° ammonium, no CNS effects
  • ophthalmic drops for glaucoma
  • duration of 4-6hrs
Reversible anticholinesterases
  • Carbaryl (Sevin, carbacide)
  • carbamate insecticides class
  • treats lice
  • high lipid solubility - so useful as insecticides
Irreversible choliesterase inhibitors
  • Echothiophate (phospholine)
  • oganophosphate with rare low lipid solubility, so not abs systemically with topical application
  • treats glaucoma where other agents cant control IOP
  • 100hrs
Irreversible choliesterase inhibitors
  • Malathion & Parathion
  • Thiophophate insecticides, rapidly absorbed and conv to active form
  • abs/conversion occur in insects and vertebrates
  • malathion: rapidly metabolized by birds and mammals to non toxic metabolites, but not in insects or for use by general public
  • Parathion: not rapidly dtoxified in vertebrates, more dangerous and not avail for public use
Irreversible choliesterase inhibitors
  • Nerve agents (gases)
  • Sarin, soman, tabun, VX used in chemical warfare
  • poisoning sx's are more severe than insecticides
  • poisoning: miosis, glandular hypersecretion, sweating, fasciculations in skeletal muscle followed by weakness * flaccid paralysis.
  • CNS cholinergic receptors - produce irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma, resp depression
  • death d/t resp failure
  • **agents age rapidly, tx window for PAM is very short**
  • prophylaxis of pyrdostigmine used if at risk from exposure.
  • PAM gives some more time to be treated with atropine or 2-pam
Toxicity of Cholinomimetics
  • Direct acting muscarinic stimulants
  • pilocarpine and choline esters cause signs of muscarinic sx: n/v/d, salivation, sweating, flushing, bronchoconstriction
  • competitive antagonist, Atropine, counters these effects
  • some mushrooms cause xs muscarinic activations: inocybe in particular
Toxicity of Cholinomimetics 
  • Direct acting nicotinic stimulants: Nicotine
  • tobacco & insecticides w/ nicotine are the only CC of this poisoning.
  • Nicotine: readily absorbed, v. toxic.  Toxic dose = 40mg, 1drop, 2 cigarettes
  • also an emetic, limits amount of alkaloid entering system (acute tox is rare)
  • in smoking, nicotine is addictive component and increases risk of CVdisease and SCD, and contributes to recurrent peptic ulcers and GE reflux disease.
Toxicity of Cholinomimetics
  • Direct acting nicotinic stimulants
  • Sx's: central stimulant actions - convulsions, coma, death; respiratory paralysis d/t depolarizing block of muscle nicotinic receptors, HTN, arrhythmias
  • tx: symptomatic management, antagonizing muscarinic activation (↑ parasymp tone by activating ganglia) with atropine.
  • central effects treated with diazepam.
  • depolarizing block at NMJ not responsive to drugs, ventilation may be necessary
Toxicity of Cholinomimetics 
  • Cholinesterase inhibitors
  • Home pesticides major source of toxicities
  • identify acute intox and treat promptly
  • dominant initial signals d/t muscarinic excess: miosis, salivation, sweating, bronchoconstriction, V/D.
  • CNS involvement: seizures, depolarizing muscle block causes resp failure
  • tx: maint respiration
  • decontamination
  • parenteral atropine in large doses and PAM to regenerate cholinesterases , benzodiazepines to prevent seizures
Cholinergic activating agents
Direct - bind and activate receptor
Indirect - inhibit degradation of ACh by AChE
  • Muscarinic receptors
  • Nicotinic receptors
Muscarinic receptors
  • 7 transmembrane domains
  • coupled to G proteins
  • 5 subtypes: M1-M5
  • agonists activate GPCR
  • M1 & M3 are stimulatory, M2 is inhibitory
Muscarinic receptors:
  • Stimulatory: M1
  • Nerves and glands
  • coupled to Gq & G11 proteins
  • increases IP3 & DAG production - increases intracellular calcium and activate PKC
  • slow EPSP, ganglionic potentiation
  • ↑ gland secretion (salivary, gastric)
Muscarinic receptors:
  • Stimulatory: M3
  • Glands, smooth muscle, endothelium
  • Coupled to Gq & G11 proteins
  • increase IP3 & DAG production - increases intracellular calcium and activate PKC
  • ↑ secretions, contraction of smooth muscle, relax sphincters (GI/bladder), release NO from vascular endothelium
Muscarinic receptors: 
  • Inhibitory: M2
  • Heart, nerve terminals, smooth muscle
  • coupled to Gi & Go proteins
  • decreases AC - ↓cAMP, ↓intracellular Ca++, ↑ K+ channels
  • Slows HR and force of contraction (atria, SA node), decreases contractile force of ventricle
Nicotinic receptors
  • Pentameric ion channels
  • 2ACh must bind for conformation change that makes channel for cation entry and subsequent depolarization/activation of the cell
  • two types: Nn and Nm
  • both result in fast, excitatory postsynaptic potentials
  • post activation states: close of channel then desensitization (biphasic)
  • they are usually systemic and nonselective - resulting in a broad spectrum of effects.
Nicotinic receptors:
  • Nm
  • Muscle type
  • @ NMJ - muscle contraction
Nicotine Receptors:
  • Nn
  • neuronal nicotinic receptors on neurons
  • send AP to postganglionic neuron and secrete catecholamines from adrenal medulla
  • throughout CNS, on postsynaptic neurons, ANS ganglia, on chromaffin cells
Direct agonists:
2 classes
  • esters of cholines (ACh, methacholine, bethanecol, carbachol)
  • Alkaloids (muscarine, nicotine, pilocarpine)
  • All agonists have longer effect than ACh because they're not hydrolized by AChE
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