Med chem - glaucoma part 1 Flashcards
explain what glaucoma is
elevated IOP that eventually leads to irreversible damage to the optic nerve and permanent loss of vision (blind)
IOP is also referred to as….
ocular hypertension
what are the 2 main types of glaucoma
open angle and closed angle
open angle more common
increased IOP is a result of what?
A buildup of aqueous hemor
what is aqueous humor and is it produced in the front of rear of the eye
clear
front of the eye
true or false
aqueous humor is continuously produced
true
name 2 drainage systems where aqueous humor normally exits the eye
trabecular meshwork
uveoscleral pathway
name 7 classes of drugs used for treating glaucoma
muscarinic agonists/AChE inhibitors
sympathomimetic amines
CAIs (carbonic anhydrase inhibitors)
Beta blockers
a2 adrenergic agonists
prostaglandin F analogs
ROCK inhibitor (Rho kinase)
name 2 muscarinic agonists used for treatment of glaucoma
(direct acting - not cholinomimetics)
carbachol
pilocarpine
name a AChE inhibitor used for treating glaucoma
(indirect cholinomimetic)
physostigmine
name 2 sympathomimetic amines used for treatment of glaucoma
epinephrine and dipivefrin
who do CAIS (carbonic anhydrase inhibitors) work in the treatment of glaucoma
they reduce the production of aqueous humor in the eye
name 4 CAIs used in treatment of glaucoma
acetazolamide
methazolamide
brinzolamide
dorzolamide
how do beta blockers work in glaucoma treatment
slow the production of aqueous humor in the eye to reduce intraocular pressure
name 3 beta blockers used in glaucoma
betaxolol
timolol
levobunalol
how do alpha2 adrenergic agonists work in glaucoma
reduce aqueous humor production and increase drainage
name 2 alpha 2 adrenergic agonists used in glaucoma
brimonidine
apraclonidine
how do prostaglandin F agonists work in glaucoma treatment
they increase the outflow of aqueous humor from the eye
name 6 prostaglandin F agonists used in glaucoma treatment
bimatoprost
travaprost
latanoprost
unoprostone
tafluprost
latanoprostene bunod
how do Rho kinase (ROCK) inhibitors work in treating glaucoma
increases aqueous humor drainage
give an example of a ROCK inhibitor
netarsudil
true or false
carbonyls and ester groups are essential for ACH activity
FALSE
bc ketones and ethers are also potent (muscarine)
give 3 reasons why acetylcholine is not a good drug
-not specific - will activate all kinds of cholinergic receptors in the body with no selectivity
-quaternary ammonium group is not good bc it won’t permeate across membrane - very polar
-has an ester, which is extremely susceptible to hydrolysis
therefore, to produce direct muscarinic agonists, we need to alter the structure
explain the structure of carbachol just by looking at the name
what is the reasoning behind this
carbamic acid + choline
carbamic acid avoids ester hydrolysis, which is an issue with pure acetylcholine
difference between acetylcholine structure cv carbachol
only difference is acetylcholine has terminal CH3 and carbachol has terminal NH2
purpose is to avoid ester hydrolysis
how do pilocarpine and carbachol work in glaucoma
increase the outflow of aqueous humor via the trabecular pathway
when carbachol was discovered, the only difference was bioisoteric replacement of….
CH3 in ACh with NH2 (amino) in carbachol
true or false
pilocarpine is NOT structurally derived from acetylcholine, but carbachol is
TRUE
TRUE OR FALSE
pilocarpine is a natural product
true
derived from plant pilocarpus jaborandi
explain the mechanism of AChE (without any drug)
the nucleophile – AChE-Ser-OH
the lone pair on OH attacks the CARBONYL on acetylcholine, forming a highly unstable tetrahedral intermediate, and effectively kicking out the leaving group
this forms
AChE-Ser-O bound to acetate + choline
the Acetylcholinesterase-acetate complex undergoes hydrolysis in MILLISECONDS – and the enzyme is back in its active form
true or false
physostigmine is not a natural product
false - it is an alkaloid obtained from seeds of physostigma venenosum
what amino acids are contained in AChE enzyme that are critical for binding acetylcholine
histadine
aspartate/glutamate
serine
true or false
physostigmine is considered an INDIRECT cholinomimetic
TRUE
indirectly increases acetylcholine by inhibiting acetylcholine esterase
true or false
physostigmine is an irreversible inhibitor of AChE
false
reversible - even tho covalent bond, still hydrolyzed back to active enzyme in minutes
explain how physostigmine works to inhibit acetylcholine esterase
instead of the OH on AChE attacking acetylcholine, it attacks the carbonyl on phystostigmine instead
a COVALENT BOND is formed to the carbonyl component of the drug
this undergoes hydrolysis back to the active enzyme in MINUTES rather than milliseconds. keeps the enzyme bound and inactive for a longer period of time, causing acetylcholine to not degrade as quickly
the enzyme is CARBAMOYLATED instead of just ACETYLATED, as in the case if no drug was present
this causes more contraction of the ciliary muscle and thus increased outflow of aqueous humor through schlemm’s canal
physostigmine is indicated for what type of glaucoma?
how does it work?
open angle glaucoma
contracts ciliary muscle, causing increased aqueous humor output into schlemm’s canal
which are better acetylcholine esterase inhibitors and why –
aryl carbamates or alkyl carbamates
ARYL CARBAMATES
they have a better leaving group due to resonance on aromatic ring
phenoxide better leaving group than alkoxide
name 2 sympathomimetic amines for glaucoma
epinephrine
dipivefrin
name 2 ways that sympathomimetic amines help to treat glaucoma
-reduce aq humor formation
-decrease resistance to outflow of aq humor
explain the relationship between epinephrine and dipivefrin
dipivefrine is the PRODRUG for epinephrine
it has 2 pivalic acids which are hydrolyzed by corneal esterase to produce Oh’s instead – structure of epinephrine
dipivefrine is well absorbed through the cornea and epinephrine is poorly absorbed bc of the polar OH groups
there are 4 carbonic anhydrase inhiibtors
break them down into which are given topically and which are given orally
oral - acetazolamide and methazolamide
topical - dorzolamide and brinzolamide
how do carbonic anhydrase inhibitors work?
the carbonic anhydrase enzyme is involved in the formation of aqueous humor
thus, by inhibiting it, the rate of aqueous humor formation is reduced in the hopes that intraocular pressure will decrease
what component must potential drugs have in order to inhibit carbonic anhydrase enzyme
a sulfonamide group - aryl or heteroaryl
explain the MECHANISM in which carbonic anhydrase inhibitors reduce intraocular pressure
within the eye, CO2 + H2O is converted to carbonic acid (H2CO3) by carbonic anhydrase. this then dissociates into bicarbonate ions (HCO3-) and H+
these bicarbonate ions in the eye are hyperosmotic compared to the plasma, thus water from capillaries is attracted to the area and intraocular pressure increases
by inhibiting carbonic anhydrase, we’re limiting the number of bicarbonate ions produced, and thus less water is attracted and intraocular pressure decreases. reduced aqueous humor formation
the aqueous humor is rich in ___ and ___ ions
sodium and bicarbonate
formula for carbonic acid
H2CO3
where is the carbonic anhydrase enzyme located
in the cornea
“pharmacophore” for carbonic anhydrase inhibitors
aryl or heteroaryl sulfonamide group
explain mechanism in which dorzolamide and other CAIS inhibit Carbonic anhydrase
the sulfonamide is CRTICIAL for inhibition
chelates with zinc and hydrogen bonds with threonine 199 on the enzyme
INHIBITS CATALYTIC ACTIVITY OF CARBONIC ANHYDRASE ENZYME
Name the beta blockers for glaucoma
which are b1 selective and which are nonselective?
b1 selective – betaxolol
nonselective - timolol, levobunolol
mechanism in which beta blockers help with glaucoma
lower IOP by reducing production of aqueous humor
pharmacophore for beta blockers for glaucoma
aryloxylpropanolamine
name 2 alpha2 adrenergic agonists
brimonidine
apraclonidine
mechanism of alpha2 adrenergic agonists in glaucoma
reduce production of aqueous humor AND enhance outflow via uveoscleral pathway
