Cholinesterase

Reactivators
--adrugthatreactsdirectlywiththe
alkylphosphorylatedenzymetofreet
heactiveunit

Pralidoxime chloride

IUPAC Name:
(1-methylpyridin-2ylidene)methyl]-oxoazanium

Pralidoxime chloride
Other Names:
2-formyl-1-methylpyridinium chloride
oxime
2-PAM chloride
2-pyridine aldoxime methyl chloride

Pralidoxime chloride
White, nonhygroscopic,
crystalline powder
Soluble in water (1g in less
than 1 mL)

Pralidoxime chloride
USES:
Antidote for poisoning by parathion and
related pesticides
Effective against some phosphates that
have a quaternary nitrogen
Effective antagonist for some
carbamates (neostigmine,
methylsulfate, pyridostigmine bromide)

Pralidoxime chloride
Structure Activity Relationship:
The functional group, the oxime moiety
remains essential for the activity of the
reactivator
Its position on the heteroaromatic ring
influences the reactivation ability
The increased quantity of the oxime
moieties in the molecule of AChE
reactivator is not essential for reactivation
and it usually increases toxicity

Pralidoxime chloride
Structure Activity Relationship:
The mono-oxime compounds showed similar or
higher reactivation ability compared to bisoximes
The length and constitution of the linker are
the most important factors. For OPPs, alkylene
linkage from 3 to 5 equivalents of C-C bond
was found to be optimal for reactivation
The addition of a double bond or an aromatic
moiety increased the reactivation ability, but it
also increased reactivator toxicity

Pralidoxime chloride
Structure Activity Relationship:
Concerning the non-oxime part of the
molecule, various functional groups may be
introduced to increase the reactivation
ability
3- or 4-carbamoyl, methylcarbonyl or
isoquinolinium moieties

Indeed from a toxicity point of view, the

carbamoyl, carboxyl and methylcarbonyl
moieties were found to be very promising
candidates

Pralidoxime chloride
Biological half-life in human is
about 2 hours
Effectiveness is a function of its
concentration in plasma, which
reaches a maximum 2 to 4 hours
after oral administration

Pralidoxime chloride
ROUTE OF ADMINISTRATION:
Intramuscular
Subcutaneous
Intravenous
*Poisoning: effective if given within a few
hours

Pralidoxime chloride
Example:

Pralidoxime Chloride
Dosage Form:Injection
(intramuscular)

Adrenergic Neuron
Blocking Agent
onethatinhibits
thereleaseofnorepinephrine
frompostganglionic
adrenergicnerveendings.

Guanethidine

IUPAC Name:
2-[2-(azocan-1-yl)ethyl]guanidine

Guanethidine
Route of action:
Enter the adrenergic neuron by the
uptake-1 process
Accumulate within the neuronal storage
vesicles
They bind to the storage vesicle
Stabilize the neuronal storage vesicle
membrane making them less responsive
to nerve impulses

Guanethidine
Neuronal blocking drugs possess a
guanidino moiety
The presence of the more basic
guanidino group than the ordinary amino
group means that at physiological pH are
essentially completely protonated
Do not get into the CNS thus they have
no central effects seen with other
antihypertensive agents

Guanethidine
It contains two basic nitrogen so it
can form:
Guanethidine monosulfate --C10H22N4
H2SO4
Guanethidine sulfate -- [(C10H22N4)2
H2SO4]

Guanethidine
Example:

(AMDIPHARM)
Used as an antihypertensive drug

Guanethidine
Activity Structure Relationship:
Lipophylicity, basicity, and fitting
Heteroatom- and hetero ring

The optimum distance between the

two active poles of the guanethidine
molecules is ensured by the
connective ethylene bridge of the
side chain

Guanethidine
Activity Structure Relationship:
Decrease of the ring size in the nitrogencontaining heterocycles
Reduced or completely eliminate the
effectiveness

Enlargement to a nine or ten-membered

ring
Milder activity

Change of heteroatom to oxygen

Guanoxan and derivatives

Guanethidine
Activity Structure Relationship:
Replacement of the guanidine group by
other nitrogen-containing moieties
(amino group, semicarbazide, carbazide)
Less active hypertensive

Substituition of the guanidino-nitrogen

with alkyl group
Mildly effective or inactive compound, due to
the decreased reactivity of the nitrogen

Methyldopa

IUPAC Name
2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic
acid

Methyldopa
It differs structurally from L-DOPA
only in the presence of a -methyl
group
AADC inhibitor
Decreases the concentration of DA,
NE, E, and serotin in the CNS and
periphery

Methyldopa
Mechanism of action:
Not caused by the AADC but, rather, by
the metabolism in the CNS to its active
metabolite (-methylnorepinephrine)

Methyldopa
Route of action:
Transported actively into CNS via an
aromatic amino acid transporter
Decarboxylated by AADC in the brain to
(1R, 2S)--methyldopamin
Stereospecifically -hydroxylated by
DBH to give the (1R,2S)-methylnorepinephrine
This active metabolite is a selective 2agonist because it has correct (1R,2S)
configuration

Methyldopa
It is currently postulated that methylnorepinephrine acts on 2receptors in the CNS to decrease
sympathetic outflow and lower blood
pressure
Used only by oral administration
because its zwitterionic character
limits its solubility

Methyldopa
Structure Activity Relationship:
Elongation of the side chain by even one
carbon atom completely abolishes the
hypertensive activity
The significance of the phenolic group in
the receptor binding is reflected by the
findings that etherification or
substitution causes a reduction of
hypertensive activity

Methyldopa
Example:

Aldomet

Reserpine

IUPAC Name:
Methyl-11,17-dimethoxy-18-[(3,4,5trimethoxybenzoyl) oxy]-yohimban-16carboxylate

Reserpine
NT Depleter
Indole alkaloid from the root of
Rauwolfia serpentina found in India
Susceptible to decomposition by light
and oxidation
Metabolized through hydrolysis of the
ester function at position 18 and
yields methyl reserpate and 3,4,5trimethoxybenzoic acid

Reserpine
Depletes:
the vesicle storage of NE in sympathetic
neurons in PNS
Neurons of the CNS
E in the adrenal medulla
Storage of serotin
DA in their respective neuron in the
brain

Reserpine
Structure Activity Relationship:
When the trimethoxybenzoyl group was
replaced with other 18-O-acyl groups,
very few of the resulting products had a
strong hypertensive activity similar to
that of reserpine.
-diethylaminoethyl substitution of
reserpine did not cause a weakening of
the hypertensive activity
Highly polar reserpic acid has no activity

Reserpine
Structure Activity Relationship:
The N-alkyl derivative of reserpine are
inactive
Unsaturation in rings abolishes the
hypertensive activity

Reserpine
Example:

Antipsychotic drug