Cholinergic

Question 1

Carbamic Acid Drugs

Answer 1

** these are AChE inhibitors, they slow the process of ACh binding to AChE to the point that it allows ACh to remain in synapse longer and continue producing effects** reversiblePhysostigmineNeostigmine/PyridostigmineRivastigmine/Donepezil

Question 2

Donepezil

Answer 2

AchE inhibitor, Carbamic Acid Ester Rivastigmine/AriceptTx Alzheimer’s (degneratin of cholinergic neurons in hippocampus) Cross BBB, cause build-up of ACh in areas where levels are too low Won’t work forever

Question 3

Physostigmine

Answer 3

AchE inhibitor, Carbamic Acid Ester Tertiary N – uncharged, can cross BBB Was used to treat some depressions, but no longer available GOAL: increase secretions (by having more ACh present, you increase the stimulation of secretions)

Question 4

Neostigmine

Answer 4

AchE inhibitor, Carbamic Acid EsterPyridostigmine Quaternary N  can’t cross BBBUsed to treat neuromuscular disorders like Myasthenia Gravis  increase ACh concentrations at NMJ  increase muscle strengthWide range of side effects

Question 5

Edrophonium

Answer 5

short acting AChE inhibitor with quaternary N Used in the operating room to reverse neuromuscular blockade after anesthesia Lasts about 10-15 min Reversible The only short acting ACh enhancer discussed in class

Question 6

Organophosphates

Answer 6

phosphate atom double bonded to O, bonded to two R groups + F atom Irreversible bond with serine residue of ChE  completely inactivates it ** CAN BE VERY BAD because have long duration of actionOnly official drug here is Echothiophate (never given orally, only as eye drops as tx for Glaucoma; similar to Carbachol)** Some can also be used as insecticides! Parathion Malathion – less potent

Question 7

Muscarine

Answer 7

toxin from muschroom Binds only to muscarinic receptors (4.4A apart)Activates PSNS response (“rest and digest”), sweat glands (SNS), causes NO mediated vasodilation when administered (but remember, there is no innervation)

Question 8

Carbachol

Answer 8

NH2 rather than CH3 next to carbonylHinder hydrolysis by AChE  longer duration of action Low doses at muscarinic receptors (CV, PSNS) High doses at nicotinic receptors (ganglia, adrenal medulla, NMJ) ** eye drops! For glaucoma Dilates pupil, stimulates ciliary m. Opens Canal of Schlemm to allow for more drainage

Question 9

Bethanechol

Answer 9

has both beta-methyl group and NH2; combination of the two aboveGiven orallyUsed following surgery if got close to the GI tract (paralytic ileus) Gets GI motility going again (recover peristalsis) Long duration

Question 10

Nicotine

Answer 10

Used in smoking cessationAs ganglionic stimulant, it has potential side effects  including on adrenal medulla, increased BP & HRBinds to nicotinic receptors (5.9 A apart)Two subtypes:Nicotinic Subneuronal: Activates preganglionic PSNS and SNSNicotinic Submuscular: muscle contraction at NMJ, Epi and NE release at Adrenal Medulla

Question 11

Anticholinergics/Antimuscarinics

Answer 11

AtropineTolterodine/OxybutyninCurare

Question 12

Tolterodine/Oxybutinin

Answer 12

AnticholinergicAlso called: Detrol, oxybutynin, DitropanTreat weakness of bladder walls, overstimulation of bladder, urge to urinate – by blocking the effects of ACh, you are blocking the contraction of the bladder muscle and preventing urinationTaken orally, associated with side effects common to anti-muscarinic drugs including dry mouth and visual disturbances

Question 13

Atropine

Answer 13

Competitive inhibitor, classic ACh antagonist Absorbed orally, crosses BBB (Weak base – ionized and non-ionized) Initially used to treat gastric ulcers, but it was found to cause constipation** this is in the antidote kit against chemical warfare, counteracts the effects of the AChE (Sarin) on the brain, heart, trachea, and GI tract by competitively inhibiting the ACh that is now present in excess because it is not being metabolized  use a “heroic amount” + Pralidoxime

Question 14

Curare

Answer 14

Blocks NMJ, NM (submuscle) sites Competitive blocking drug Blocks nitrogen binding sites at submuscular receptors USED FOR ANESTHESIA: Give curare-like drugs to produce muscle paralysis during surgery 10-C distance between the N

Question 15

Hexamethonium/Trimethaphan

Answer 15

2 N groups separated by 6 carbons (sounds like subneuronal subgroup!)Not on the market anymoreBlock ganglia & adrenal medulla (competitive antagonist)  preventing release of NE and Epi, this prevents the sympathetic tone to the blood vessels and they will vasodilateTreat severe hypertension (i.e. in the ER when someone comes in hypertensive crisis)

Question 16

Muscarinic Agonists

Answer 16

limited used for Glaucoma & after GI surgeryMethacholineCarbacholBethanechol

Question 17

Drugs that block at Nicotinic Subneuronal sites

Answer 17

HexamethoniumTrimethaphan

Question 18

Sarin

Answer 18

AChE Inhibitorchemical warfare agent, organophosphate, essentially irreversible AChE inhibitor, toxin Phosphorylation of AChE makes it difficult for H20 to displaceNerve gas that causes deathMassive ANS storm – whatever system predominates, DOMINATES

Question 19

Pralidoxime

Answer 19

This is a potent nucleophile, displaces AChE inhibitorsin the antidote kit, breaks the bond between the nerve agent and cholinesterasemust be administered before the nerve gases’ impact becomes permanent

Question 20

ACh

Answer 20

Not good as a drug because it is not specificacts at all cholinergic sites – neurons (N), NMJ (N), adrenal medulla (N), sweat glands (M), postganglionic PSNS neurons (M) Vasculature also has receptors – indirectly? (M) Rapid degeneration because of AChE Not well absorbed (polar)