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266 Cards in this Set

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The extent of ionization of a drug is important since generally the UNCHARGED form of a molecule is
the form permeating membrane
What are the water-soluble forms
ionized
What happens when a drug is TOO water-soluble
cannot more from stomach to circulation
HA====H+ + A-, the farther this equilibrium lies to right
STONGER the acid is
Anything stabilizing A- (more H's) will shift the equilibrium to
RIGHT increase acid strength
How do substutents affect the acidicty of aliphatic acid such as CH3-COOH then ClCH2COOH
make more acidic
Activity of sedative adn hypnotic agents are depend upon
ADME
For absorption and elmination, must drug have polar and non-polar functionalilty
YES
For metabolism/elimination 3 alcohol comparted to 1 alcohols for sedative/hypnotic agents
3 alcohols are longer lived
For metabolism of sedative/hypnotic agents what are 2 ways are longer lived
3 alcohols
Amides
Which live longer for sedative/hypnotic agents (amides or esters)
AMIDES
Aldehydate put in water form
hydrate in water
What is 1st sedative hypnotic
tricholoracetaldehyde
With most aldehydes the hydrate is
a non-isolable product in equlibirum with aldehyde
Which is more polar choloral hydrate or trichloroacetaldehyde
hydrate
When an alcohol is added to an aldeydate what is formed
hemiacetal
When 2 alcohols are added to an aldehyde what is formed
acetal or chloral diethyl acetal
Which is the most lipid-soluble in Tricholoracetaldehyde reaction
acetal
What compoents distrubtes more readily to brain and more potent sedative
chloral diethyl acetyl
What is the active metabolite of chloral
trichloroethanol
What is the inactive metabolite of of chloral
trichloracetic acid
3 Acetaladehyde will spontaneously
trimerize on standing
How can one obtain an aldehyde from a trimer or paraldehyde
heat solution
Ethanol is a sedative, but POOR, it requies a large dose and is rapidly metabolized, the potenct of ethanol can be imporved by
making is more lipophilic and less susceptible to metabolism
How can ethanol be made more lipophilic and less susceptible to metabolism
Increase the number of carbons to 7, adding a carbon-cabon-carbon double bond, adding a halogen (CL), and making a primary alcohol a 3 alcohol
What is the result of increasing # of carbons to 7, adding a carbon-carbon double bond, adding a halogen (CL), and making primary alcohol tertiary
ethclorvynol
Barbiturates were developed in 1900s after chloral, and are derivates of
barbituric acid
What type of receptors does barbiturates interact with
gaba/chloride ionophore complex
How many acidic hydrogens are there is barbuturic acid
2
The hydrogens at what position in barbituric acid are most acidic
at C5- and ionization is resoance-stabilized PKA 4
What is the pka of the hydrogens at N3
much less acidic pka 7
What must barbiturates be to enter the CNS
50% unionzied to enter CNS
If Barbiturates must be 50% unionized to enter CNS, what acidic hydrogens must be replaced by other substutents
both hydrogens at C5
Activate barbiturates must be
5,5 disubstiuted
Are barbiutates (sedative/hynotic) stable in aqeous base and form
NO Carbonyl and 2 NH2, and 2 CO2 connected together
Is barbituate itself chiral
NO
Barbiturates duration of action is a function of
lipid solubility
At 5th carbon of barbiturate adding 4-6 carbons does what
more water-soluble duration of 8-12 hours
At 5th carbon of barbiturate adding 6-8 carbons does what
more lipid soluble duration 6-8 hours (SHORTER DURATION OF ACTION)
More lipophilic barbiturates have
a shorter duration of action
What happens are C5 when there is >10 carbons
convulsant
Can there be a H at 5th carbon
NO
What would give a barbiturate an ultra-short duration of action
a Thioketone, at C2
Longer acting barbiturates are more
water-solulbe
Mephobarbital is rapidly...
N-demethlylated to phenobarbital
Is P-hydroxylation of mephobarbital enantioselective (have STEROCHEMISTRY
YES-all para-hydroxylation has steriochemistry
What effect does a benzene ring have on a barbiturate at C5
benze forms pie clouds above and below plane, and benze b/c polarized induced dipole
Benzene forms a pie cloud above and below plane, so beneze b/c
A polorized induced dipole--makes more water soulbe
Barbiturates unergo what type of metabolism
extensive hepatic metabolism
What is common metabolism method of CYP450 on phenobarbital
para hydroxylation (adding of an OH to aromatic ring
Does any oxidation to barbiruates destory activity
YES
Benzodiazepine were discovered accidently looking for new
methaqualone analogs
Benzodiazepines were 1st drugs availbable for treatment of
anxiety
Receptor site of Benzodiazepines
gaba/chloride ionophore complex (GABA-A)
Do benzodiazepines have ionizable portions like barbituares
NO
Are benzodiazepines water soluble
very little water soluble
If a benzodiazepines are SO WATER INSOLUBLE, how are they absorbed
the gut has a large SA so eventually absorbed
Diazepam can be broken down into
Temazepam and FAST nordiazepam
Diazepam rapidly b/c nordiazepam, what is benfit
Has no hydroxy 3--so UNDERGOES VERY SLOW metabolism to oxazepam (40hrs)
Temezaepam then is converted into
oxazepam by N-demethlayyion
What is duration of action of oxazepam
short DOA, undergoes glucuronide and becomes glucuronide
What are CYP450 of benzodiazepines
CYP 1A2, CYP3A4, CYP 2C9 and 2C19
All benzodiazepines, with extensive CH3 at C1 become
nordiazepam by N-dealkylation and have LONGER DOA
What do all short acting benzodiapines have
a hydroxyl at C3
Flunitrazepam is AKA, and properties
Date-rate drug with a nitro group and F--makes lipid soluble and RAPID onset of action
The nitro goup of flunitrazepam is RAPIDLY
reduced to an amino group and acetylated
What are 2 ways Benzodiazepams undero metabolism
N-demethlation and C3 oxidation
Where do barbiurates undergo metabolism
C5--of beneze ring or alkyl chain oxidation
Triazolam is rapidly alpha hydroxlated to waht
a partially active intermediate by CYP3A4
What is a non-benzodiazepine Gaba-A agonists
Zolpidem (ambien), zoleplon (sonata), and eszopiclone (lunesta)
What is Zolpidem
an imidazopyridine
What is pka of Zolpidem and onset of action
6.2 adn rapid absoprtion
What type of metabolism does Zolpidem undergo
benzylic oxidation,
After Zolpidem undergoes benzylic oxidation, to a primary alcohol, what happens
Alcohol dehydrogenase oxidation to finally a carboxylate
What is zaleplon
a pyrazolopyrimidine
What is eszopiclone (lunesta)
a cyloprrolone
Do anticonvulsants bear great structual similairty to
barbituates
The discovery of what in the 1970's helped explain why we have morphine receptors
peptides
What what the model that orinally proposed morphine receptors
Beckett model
Endogenous opiate agoinsts arise from
processing of large precursors
What is the principal constituent of opium
morphine
What is opium
dried exudate of Papaver somniferum
Morphine was isolated in 1805, and was first
alkaloid
Only one enantiomer of morphine is
active
How many rings is morphine
5
What are locations of Morphine modifcations
3 OH, 6 OH, 7-8 double bond, 14-OH addition, and 17N-subsititution
What metabolism does Codiene undergo
O-demethylation to morphine (active metabolite)
What is inactive metabolite of MORPHINE/codeine
the product from N-demethylation by CYP3A4
Alterations of Morphine 3-OH makes
codiene
Reduction or remove of Morphine 7,8 double bound does
reduction increases potency, less chemically reactive
What is a reduction in 7,8 double bond make less chemically reactive
removal of allylic alcohol
Reduction of morphine 7,8 double bond is used in conjunction with
oxidation of 6-OH
Heroin is very lipid soluble, and is radidly hydolyzed by an esterase to
6-acetlymorphine
Is 6-acetylmorphine found in poppie seeds
NO
What type of additiove liability is heroin on 1st use
50%
What is esterased first in heroin
3-ester to OH, and carboxcilic side product
HEROIN is rapidly metabolized, in heroin fatalites where is it found
stomach contents
Morphine is metbolized into morphine 6B-glucuronide is this active as well
YES
Morphine 6B-glucuronide is 1000 flod more potetn than morphine but
doesnt enter CNS well, and is rapidly excreted in urine
Reducing double bond of 7-8, and add ketone to 6-OH does what to morphine
more potent than morphine, not as reactive, less polar so better CNS distribution
Addition of OH-14 does what
makes oxycodone which is more potent
Why is oxycodone uniquely potent
more POLAR and unlike others accumlates in brain
Changes where on morphine increase potency
removing 7,8 double bond
adding ketone 6-OH
addtion of OH14
What do you 17N-substitute
allyl
What does 17N-substitution do
mew-receptor antagoinst---throws patietn into withdrawl
What is oripavane
synthetized by diels-alder reaction to create a 6 membered ring
Changing the N-methyl substutent to an ally produces what
a powerful mew-antagoinst
What is use of Pentazocine
Kapa-agoinst--too many side effects for useful pain contorl
The enatiomers of Levophanol and Dextromethorpahn, which is inactive
dextromethorphan
What changes can you make to phenylpiperidines
N-phenylethyl substituion
What does a N-phenylethyl substitution do, example
creates a very potent- u-agoinsts--fentanyl
What happens when you add very large N-substituents to phenylpiperidines
limit CNS distribution--and works in GUT...GUT is one giant u-receptor
What are benifits of methadone
good bioavailability and maintenance of addicts
What is the active metabolite of methadone
methadol (ketone to alcohol)
How does tramadol b/c active
O-demethylation by CPY2D6
What happens to tramadol with individuals who lack CYP2D6
diminished pain relief
What is pka of tramadol
pka 9
Is tramadol more potent than morphine
nO
What is Butorphanol
strong K-agoinst and u antagoinst- with 5x activity of morphine (will casue withdrawl) Must be take IM--no oral bioavailability
Is Buprenorphine more potent than morphine
YES 20-50 mroe potent
If Buprenorphine is 20-50 X more potent why can it only produce ED50 alagesic effect of morphine
parital K-and u agoinst
Why can't Buprenorphine be taken orally--NO ORAL BIOAVAILABILITY
rapid 3-O glucuronidation
Is Naloxone an effect u-antagoinst to Buprenophrine
NO--Buprenorhpine binds to u receptor to STRONG
Benefits of Buprenorphine being a partial agoinst
cannot produce the tolerane adn addication of full u agoinsts
What emerged from antihistamine research
antipsychotics
What was first antipsychotic
CPZ chlorpromazine
What class is CPZ
Phenothiazines
What is required for phenothizaine
MUST be an EWG at C2
A 3 carbon chain with no braching
WHat happens to a phenothizaine with no EWG
NO ACTIIVTY
How do you increase the potency of phenothiazines
inrease the size of the N-substiutent
What type of receptors do phenothizaine interact with
dopamine receptor
How do you make phenothizaine water-soluble for injection
STONG di-acid
What is a very strong di-acid
ethanedisfulonic acid
What is prepared with piperazine-containing phenothiazine
bis-sulfonate salt of piperzine
The duration of action of a phenothizine can be increase with what type of phenothiazines
phenthiazines with ending with a free hydroxl
What happens to Perphenazine as it ends with a free hydroxyl
by esterfication with a long fatty acid chian
Esterfication of phenthiazine can serve as a
Sustained release form
What types of phenothizaines can be modified
ending in OH
or have piperazine
What are possible metabolisms of CPZ
N-demethlation
S oxidation to sulfoxide or sulfone
hydroxylation
What are steroisomers of thioxanthenes
cis and trans
What do thioxanthenes give rise to
geometric ISOMER--only cis is active
Must the butyrophenone be kept intact
YES
Property of Butyrophenones
very lipid soluble
What amino acid plays a role in DA receptor binding of protanted amine
aspartate
What receptor binding points for antipyschotics with 2 rings
interact with pi-pi stacking interactions
How do Butyrophenone interact with pi-pi stacking
ring--pi-pi stacking, electron interactions with carbonyl oxygen
Receptor modeling has been done using a DA receptor agoinst AKA
8-OHDOPAT
How many transmembrane segemtns are there with angoinst binding
7
What does Phenol bind to
hydrogen bonds to OH of serine 193
What does Phenyl bind to
pi-pi stacking with phenylalanine 390
What does Amine bind to
ionic interactions to aspartate
How do local anesthetics work
block sodium channels and AP
Sodium channels consits of a tetramer of units, with each having 6 transmembrane segments, where does local anesthetic bind
6th segment of the fourth unit
What is problem with cocaine
Labile ester rapidly hydrolzed
CNS--abuse problems
Vasoconstriction
Early research determines that only a portion of cocaine strucutre is needed for local anesthesia that is
aromatic ring
conjugated ester
intermediate chain
terminal amine
1st local anestestic derived was, and effects
procaine--vasodialtor
What are 4 main things needs for structure/relationship of anestethics
(aromatic ring) lipophilic
Conjugated ester
intermediate chain
polar portion (amine)
The intermediate chain needs to be
2 or 3 carbons can be branched
The polar portion is usually an amine, it is usually
teriatry amine
Local anesthetic activity increases with
increasing lipid of polar end (making an isobutyl)
What are 2 topical anesthetics only
benzocaine and butamben
How do you make a topical anesthetic
removed terminal amine--ester with 3 carbons
Procaines and esters--could not be sterilzed, so what was developed that is stable in boiling water
amide anestetheics---lidocaine
What are benefits of amide anesthethetics (lidocaine)
faster onset of action---and decrease chemical reactivity--longer DOA
What is lidocaine metabolized by
amidase
How can lidocaine be metabolized
Oxidation or methyl group
N-dealkylation
NO is a gas rapidly destroyed by
Oxygen
How is NO stored
S-nitrosylmeyhionine
Nitrous acid + alcohol=
nitrite ester
Nitric acid + alcohol=
nitrate ester
Organic nitriies seve as a source of
NO by ONE electron reductase
Organic nitrates are reduced to
nitrous acid by 2 electron reduction
RONO2 =
ROH + HONO
RONO -
ROH + NO
What is the only stereochemical nitrate
isorbidie dinitrate
Isosorbide dinatrate has 2 nitro groups, one is acessible, but inaccessible one
provides a longer duration of action
Sodium nitropursside is
a source of NO
What does NO binds to
F3+3
Sodium nitropursside NO comes off easily, replaced by
NO replace by water
What are 3 chemical approaches to lower BP
1. CNS
2. PNS
3. Renal mechanisms
What are 2 drugs that works by CNS mechanisms
1. Aldomet
2. Clonidine
Alodmet was designed as, Aldomets goal
an inhibitor of DOPA decarboxylase--goal to delete peripheral CCA
Aldomet, is a perihperal dopa decarboxylase inhibit that does what
enhances the CNS effect
alpha-methyldihydroxyphenylalanine is AKA
Aldomet
What is a zwitterion at pH 7.4
Aldomet
Aldomet is converted into
alpha-metyldopamine
Alpha-mehthyldopamine is convereted into
alpha-methylnorepeine
Alpha-methylnorepinephrine is a false transmitter--how does it act centrally
hypotensive agent
Clonidine is dervided from
guanidine
What is PKA of clonidine
8.25
What is optimal placement of clonidine
2,6 optimal placemet
What is optimal EWG for clonidine, can you can chain length
CL (alkyl or bromo substituion bad--no clonidine is optimal
What are changes that can make clonidine worse
1. Alter CL placement
2. Use another substituent
3. Increase chain length
4. Change N-ring size
What is optimal N-ring size for clonidine
imidazole
What is benefit of CL
makes lipophilic, and prevent imidzoline rotation,
What is benefit of phenyl in clonidine
phenyl decrease basicity of guanidine from 13 to 8
What can't you change the chain length of clonidine
chain length is critical to spatial match NE
What are peripheral mechanisms for reducing BP
1. Ganglionic blocking drugs
2. Reserpine
4. Guanethidine
What are properties of Ganglionic blockers
permenant cations, water soluble, no oral bioavilability, and rapidly filtered
No sutrucutral permutaitons work is RESERPINE, irrervesible after
24hrs
What do you need to do to recover from reserpine
make new vesicles
Does hydrolysis make reserpine inactive
YES
Guanethidine is essenetialy
a permant cation
How many N are protanted at a time on Guanethidine
ONlY ONE
ACE is an enzyme that contains
Zn+--similar to carboxypetidase
ACE converts
Angiotension I (10aa) to Angiotensin II (8aa)
What was the first ACE inhibitor
captopril
What does captorpil contain
SH, which binds to zinc tightly
What are the 3 componenets of ACE enzyme
HIS-ZN+, Tyr--OH and Arg NH3+
What does Enalprilat bind better than captopril to ACE (enzyme)
mimics that Transition state of Angiotensin I
How does enalaprilat mimics the angiotensin I transition state
has a tetrahydreal carbon
What does ZN coordinated
the carbonyl to be hydrolyzed
Enalaprilat has very poor bioavailability, how is this fixed
pro-drug-enalapril--has an ester
CCAs are NT released upon stimulation of the
sympathetic nervous system
What are the major CCAs
NE, Epi
What is Flight or fight response
increase HR, BP, blow flood to skeletal muscle
CCA are very polar do they esaily distrubte to CNS
NO
Where are CCAs synthetzied
central and perihperna nerve ending, and adrenochrmaffin cells
What is percursor for CCAs that is transported into CNS for synthetsis
synthetisis
Where are cCA stored
vesicles, and chromaffin cells
Action of CCAs is terminated by what
uptake
What are CCAs very sensitive to
chemical oxdiation to ortho-quinonones
Are ortho-quinonones active
NO--inactive as NT
Tyrosines is transported into CNS, the rate limiting step is
Tyrosine hydroxylase
Tyrosine is meta-hydroxlated to
DOPA
Within the storage vesicle, what happens
DA is beta-hydroxylated to norephine
The hydroxyl group of NE has sterochemsitry in what configuartion
R configuration
NE b/c Epi through
Phenylethanolamine N-metyltransferase
Where does converstion of NE-to EPI occur
adrenal chromaffin cells
CCAs exsacping neuronal uptake are metabolized by
MAO
COMT
Aldehyde reductase
ALdehyde dehtdrogenase
What are CCA interactions with B receptors
Cateocols interact with Serine hydrogen, and protanted amine interaacts iwth aspartate,
WHat does MAO do
converts primary amines to aldehydes
What does COMT do
methlates the OH groups of meta
NE b/c what with MAO
DOPGAL
NE by COMT b/c
normetanephrine
What does ALdehyde reductase do
aldehyde b/c alcohol
What does Aldehydye DEHYDOGENASE DO
aldehyde to carboxylic acid
What are the 3 adrenegric receptor substyes according to
NE, E and isproteneronol
Alpha preferance
EPI >NE >ISO
Beta preferance for
ISO>EPI>NE
What happens are size of N-substituent increases
Beta activity increases due to a lipophilic binding pocket (alpha decreases)
Phenylethanolamines is general sturucure for ALL adergergic AGOINST
What happens when you add a methyl R2 of phenylethanolamine
slows down action of MAO
What ring substitution is best for both alpha and beta agoinst
3,4 dihydroxy substitution
What happens if you only have a 3-OH
alpha activity is reduced, and Beta activity nearly eliminated
What are 3 alpha agoinsts
phenylephrine, metaraminol, and methoxamine
WHat are main characteristic of alpha agoisnt
3-0H, and small N-substitutent
When there is no aromatic hroxyls, agoinst actity may be
mixed (direct/indirect) or indirect
What are 2 properties of Al agoinst
little cardic stimulation, and not substrates for COMT--so longer acting the NE
How is methoxamine bioactivated
O-demethlation
What is another class of Al agoinst
the aryl-imidazolines
Main action of A1
vasoconstrtion
Do alpha receptors accept more strucutally diverse agoisnts
YES
What are characteristic of the aryl-imidzolines (oxymethazoline and xylometazoline)
contain a lipophilic region on aromatic ring usually ortho--or
What is required for activty of alyl-imidazoles
lipophilic functionality on the aromatic ring
What are B2 agoinsts
Bitolterol
Ritodrine
Albuterol
Terbutaline
Pirbuterol
What makes B2 agoinsts NOT SUBSTRATES for COMT
methyl addition in catechols
Catecol-containing compounds are rapidly metabolized by COMT--what can make more resistant to COMT
alterations to catecols (addition of methyl
What are Alpha agoinsts not substrates for COMT
do not have catechols
What makes the aryl-imidaolines alpha ANTAGOINSTS
they are missing the aromiatc lipophilic substitute or methylene bride connecting imidzoline ring
What is a non-selective B antagoinst
propranolol
What makes propranolol
isoproternol with an addition of an ether linkage
What does an ether linkage causes
nonselective B-antagoinst
How do you make a selective B1 antagoinsts
Ether linkage with a para substitution
What is base of Beta antagoinst
isoprotenetol--added ether linkage
More lipophilic somthing is how is cleared
by liver
The more water soluble soble somthing is
is more likely filtered by kidneys