pharchem 2

Cholinesterase Reactivators

--a drug that reacts directly with the alkylphosphorylated enzyme to free the active unit

Pralidoxime chloride

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


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


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


• 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)


• 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


• Structure Activity Relationship:– The mono-oxime compounds showed similar or higher reactivation ability compared to bis-oximes

– 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


• 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


• 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


• ROUTE OF ADMINISTRATION:– Intramuscular– Subcutaneous– Intravenous

*Poisoning: effective if given within a few hours


• Example:

Pralidoxime Chloride Dosage Form: Injection (intramuscular)

Adrenergic Neuron Blocking Agent

one that inhibits the release of norepinephrine from postganglionic adrenergic nerve endings.

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 nitrogen-containing 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 Name2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid

Methyldopa

• It differs structurally from L-DOPA only in the presence of a α-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 (α-methylnorepinephrine)

Methyldopa

• Route of action:– Transported actively into CNS via an aromatic amino acid transporter

– Decarboxylated by AADC in the brain to (1R, 2S)-α-methyldopamin

– Stereospecifically β-hydroxylated by DBH to give the (1R,2S)-α-methylnorepinephrine

– This active metabolite is a selective α2-agonist because it has correct (1R,2S) configuration

Methyldopa

• It is currently postulated that α-methylnorepinephrine acts on α2-receptors 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-[(3,4,5-trimethoxybenzoyl) oxy]-yohimban-16-carboxylate

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 3,4,5-trimethoxybenzoic 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.

– Β-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

pharchem 2

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