Pharm 1 - Cholergic Agonists (Smith)

Front 1

BBB penetration of ACh

Back 1

Poor

Front 2

Blood clearance of ACh

Back 2

Rapid.

Front 3

Hierarchy of accessibility from blood of ACh

Back 3

MOST ACCESSIBLE AT TOP
CNS (depends on fat solubility, size, charge)
Ganglia
MNJ
Parasymp postgang sites
Vascular smooth muscle

Front 4

Muscarine

Back 4

Activates ACh postganglionic parasympathetic fibers, sweath glands on vascular smooth muscle.

Front 5

Signs of muscarine poisoning

Back 5

Fall in BP due to NO generation in vascular smooth muscle.

Paradoxical bradycardia (activation of musc receptors on SA node) - would expect tachycardia bc of BP drop.

Diarrhea, urination, miosis (pupillary constriction from contraction of sphincter mucsle of the iris), bronchorrhea (increased secretions), bronchoconstriction, emesis, lacrimation, sweating (sympathetic discharge).

Front 6

Pathway of generation of NO

Back 6

NO synthase activated by ACh/muscarine and this generates NO from arginine.

NO then activates guanylate cyclase to produce cGMP.

cGMP then binds myosin light chains to relax vascular smooth muscle (causes vasodilation)

Front 7

Are muscarine or ACh good agonists?

Back 7

No - because they have many SE, cleared rapidly from blood (cholinesterases)

Front 8

Types of cholinesterases

Back 8

Acetylcholinesterase/tru CHe - found at all cholinergic junctions

Pseudo ChE/plasma ChE - Not sure of its function bc ACh doesn't normally circulate in the blood and you are healthy without it.

Front 9

Therapeutically useful musc agonists must be...

Back 9

resistant to cholinesterases

Front 10

Methacholine

Back 10

resistant to cholinesterases
Dx of asthma - becuase in them, they have bronchoconstriction with really low doses of this muscuranic agonist.

Front 11

Bethanecol

Back 11

resistant to cholinesterases
Cholinergic agonist
Used to relieve GI dysmotility.

Today it is largely replaced by metoclopramide that causes the release of ACh at the terminus.

Front 12

Pilocarpine

Back 12

resistant to cholinesterases
Tx of narrow angle glaucoma
Cholinergic agonist.

Pupillary dilatation exacerbates narrow angle glaucoma, so this causes pupillary constriction by activating muscarinic receptors on the sphincter muscle.

Front 13

Narrow angle glaucoma

Back 13

Some people born with narrow angle btwn sclera and iris and this slows drainage of aqueous humor out of the canal of Schlemm.

The humor was made from the ciliary body.

Problem is worse with pupillary dilatation.

Front 14

Sphincter iridis (circular) muscle

Back 14

Parasympathetic - causes miosis with contraction

Front 15

Dilator (radial) muscle

Back 15

Sympathetic - causes mydriasis (dilatation)

Front 16

Blockade of musc receptors on the circular muscle will cause...

Back 16

Mydriasis (dilatation)

Front 17

Blockade of adrenergic receptors on radial muscle will cause...

Back 17

Miosis (constriction)

Front 18

Ciliary muscle

Back 18

Contraction will cause less tension on the lens to round it and accomodate for near vision (ciliospasm)

Relaxation will icnrease tension on the lens to flatten it and cause accomodation for far vision (cycloplegia)

Front 19

Nicotinic agonists (direct)

Back 19

Initially have muscle fasciculations but as the [] of ACh increases, receptor repolarizes and is refractory, so you have paradoxical flaccid paralysis which can not be reversed.

The only one is nicotine (used for smoking cessation)

Front 20

Signs of nicotine poisoining

Back 20

sympathetic discharge from adrenals and possibly sympathetic ganglia.

Must support respiration bc of flaccid paralysis.

Front 21

Which is inhibited first, plasma ChE or AChE?

Back 21

Plasma - so to get px in poisoinings you can assay RBC membranes for their ChE and AChE activity.

Front 22

Structure of cholinesterase

Back 22

Esteratic site and anionic site.
When it hydrolyzes ACh, an acetyl group is covalently bound to the esteratic site.

Front 23

Edrophonium

Back 23

ChE inhibitor
Does not cross BBB
Dx of MG

Front 24

Classes of ChE inhibitors

Back 24

Edrophonium, carbamate ChE inhibitors, organophosphate ChE inhibitors

Front 25

Carbamate ChE inhibitors

Back 25

Drugs and insecticides that covalently bind ChE and slowly hydrolyze over hours.

Used to tx (not dx) MG and reverse nondepolarizing MNJ blockers.

Physostigmine - crosses BBB and can tx CNS muscarinic blockers

Neostigmine - Charged, not BBB penetrable.

Front 26

Neostigmine

Back 26

Charged, not BBB penetrable.

When treating, using too little can get you a myasthenic crisis. Too much results in depol-desens blockade (cholinergic crisis)

OD can be reversed by using a muscarinic blocker.

Front 27

Physostigmine

Back 27

crosses BBB and can tx CNS muscarinic blockers

Front 28

Organophosphate ChE inhibitors

Back 28

Drugs/insecticides (parathion or malathion) or weapons of mass destruc (sarin, soman)

Needs hundreds of hours to hydrolyze.

Reverse with pralidoxime (BUT DO NOT USE THIS WITH CARBAMATE POISONING!)

Echothiophate is another example that used to be used to tx narrow angle glaucoma.