Transcript drugs acting on Autonomic Nervous system

drugs acting on Autonomic Nervous
system
M.K.Soltan
Anatomical classification of ANS:
Sympathetic nervous system (thoracic lumber).
Parasympathetic nervous system (craniosacral).
Sympathomimetics ( adrenergic agents ) ( adrenomimetics ).
they can be further classified according to several strategies:
I] due to mode of action:
A] directly acting: with intrinsic activity on the adrenoceptors that is more or
less than NEP.
B] indirectly acting : by induction of release of NEP from adrenergic neurons.
C] mixed or dual action: that act by the two mechanisms.
II] due to chemical structure and pharmacological activity ( target
receptor in the body ):
NH2
2-phenylethylamine
H
N
N
R
2-immidazolene
phenyl ethyl amine derivatives:
H3C
N
H

1
4
H3C
OH
H3C
2
N
H
OH
3 OH
H 3C
HO
H3C
H3C
CH3
N
H
OH
OH
terbutaline from tert-butyl
CH2OH
OH
Salbutamol or albuterol
H3C
NH
2 OH OH and NHCH3
H3C 1
must be in the same
3
side to be in
erythro form
ephedrine
OH
HO
OH
OH
OH
OH
epinephrine or adrenaline isoprenaline from isopropyl
CH3
N
H
N
H
H3 C
OH
H 3C
H3 C
orciprenaline
H 3C
N
H
OH
OH
phenylepherine
Stability of adrenaline: adrenaline is photosensitive, exposed to auto
oxidation that is catalyzed by light,
Autooxidation by O
in air and light
to overcome this problem:
adrenochrome, toxic ) keep in amber color glass,
resistant to light.
pink in color
) use antioxidant like vitamin C
or sodium bisulfite.
) Catechol replaced by resorcinol.
SAR. Directly acting phenyl ethyl amines.
1) Concerning length of carbon chain:
n = 0, aniline with no pressor activity
n = 1, benzylamine, very weak PA
n = 2, —CH — weak pressor
n
n = 3, same PA of n = 2, —CH2CH2— but with higher toxicity.
n = 4, no pressor activity.
2) concerning R group:
R = H, mainly pressor activity upon Stimulation of α-receptors.
R = CH3, equal affinity to both α and β receptors, so has both pressor and bronchodilator
activity.
R = isopropyl or tert-butyl groups give compounds with mainly broncholdilator activity due
to β-receptors activation
3) substitution of α-carbon (near NH2 )
by methyl group leads to the following :
A] retard MAO metabolism so increase duration of action.
B] decrease pressor activity due to decreased affinity to α-receptors.
C] increase lipophilicity so increase CNS stimulant activity.
4) substitution of β carbon atom by OH group in the form of levo (-) isomer is
very important: why?
As OH in this stereochemistry aid in the drug - α-receptor interaction by H-bond
, and this can be proved by the absence of activity of adrenalone where β carbon is
in the form of carbonyl group.
Also desoxyepinephrine is equal to dextroepinephrine in pressor activity.
5) concerning the two phenolic hydroxyl groups:
dihydroxy derivative is better than monohydroxy in activity,
favored position for dihydroxy is 3,4 that gives higher activity but less DOA than
3,5.
favoured position for monohydroxy is 3.
6) concerning drug receptor interaction:
a-benzene ring is flat surface for van der walls interaction with similar flat surface
in the receptor.
b- amino group act as cationic site to form ionic bond with anionic site in the
receptor that may be carboxyl group of acidic amino acid ( glutamic acid or
aspartic acid ).
c- OH groups play an important rule in the drug receptor interaction by forming
H-bonding with the receptor.
Sketch for (-)-adrenaline- receptor interaction.
H
H3C N
H
OH
H
OH
OH
2- Immidazolene derivatives
N
N
1
2N
H
1
2N
H
naphazoline
tetrahydrozoline
Naphazoline = 2-(1-naphthylmethyl)-2-immidazoline.
Tetrahydrazoline = 2-( 1,2,3,4-tetrahydro-1-naphthyl)-2-immidazoline.
α-adrenergic blockers.
1
NH
1
NH
tolazoline
N
2-benzyl-2-immidazoline
N 2
phentolamine
2
2-[N-(p-tolyl)-NOH m-(hydroxyphenyl) amino
methyl]-2-immidazoline
N
they are used in hypertension and in
diagnosis of pheochromocytoma
H3C
β-adrenergic blockers
H3C
H3C
OH
H
N
1
2
O
3
propranolol
1
H3C
H3C
H
N
OH
1
2
3 O
Atenolol
O
NH2
Parasympathomimetics
directly acting cholinergic agent
H3C
CH3
N
H3C
CH3
O
O
Cl
Acetyl choline chloride
H3C
CH3
N
H3C
1) surgical procedure on the anterior eye segment
2) Produce miosis after cataract surgery.
CH3
O
O
Cl
(2-hydroxyethyl ) trimethyl ammonium
chloride acetate.
CH3
(2-hydroxypropyl ) trimethyl ammonium
chloride acetate.
Methacholine chloride
H3C
H3C
Cl
CH3
N
NH2
O
O
Carbachol chloride
(2-hydroxypropyl) trimethyl ammonium
chloride carbamate.
H3C
H3C
CH3
N
NH2
O
O
Cl
CH3
Bethanechol chloride
(2-hydroxypropyl) trimethyl ammonium
chloride carbamate.
1) Urinary retention.
2) Reflux oesophagitis.
indirectly acting cholinergic agents ( choline esterase inhibitors ).
H3C
Br
N
CH3
N
CH3
O
O
3-hydroxy-1-methyl pyridinium bromideN,N-dimethyl carbamate.
pyridostigmine bromide
1) orally used for Myasthenia Gravis, less toxic
than neostigmine.
2) antagonize neuromuscular blockers.
3) treatment of paralytic ileus.
Antimuscarinics (parasympatholytics) (cholinolytics).
Chemical classification of antimuscarinics:
A] amino alcohol derivatives:
A.1) amino alcohol esters: ( ester = amino alcohol + acid ).
I] natural solanaceous alkaloids: atropine sulfate, hyoscyamine,
scopolamine HBr.
II] synthetic analogs of solanaceous alkaloids:
synthetic esters of tropine and scopine: homatropine HBr, scopolamine butyl
bromide.
synthetic esters of other amino alcohols: cyclopentolate HCl, oxyphencyclimine
HCl
poldine methyl sulfate, oxyphenonium bromide, propanthelin bromide.
A.2) amino alcohol ethers: ( ether = amino alcohol + other alcohol ).
Benzotropine mesylate, chlorophenoxamine.
B]amino alcohols: procyclidine HCl, benzhexol HCl.
C] amino amides: isopropamide, tropicamide.
A] amino alcohol derivatives:A.1) amino alcohol esters:
H
N
Chemical nomenclature:
tropine(+)tropate sulf ate
1,53tropanol
tropate sulf ate
racemic mixture of (+) and (-) hyoscyamine
CH3
HO
-2
SO4
O
O
*
2
Atropine sulf ate
2) synthetic esters of other amino alcohols:
2-hydroxyethyl diisopropyl methyl ammonium
bromide
xanthene-9-carboxylate.
Propanthelin bromide
2) amino alcohol ethers:
chlorphenoxamine
-(methyl-phenyl
-p-chlorobenzyloxy)
ethyl dimethyl amine

they are used as: )antihistaminic )treatment of parkinsonism
in which Ach level increase,and dopamine decreaese in CNS.
amino alcohols:
HO
1
2
3
Cl
N
H
p rocyclidine HCl
-cyclohexyl--phenyl-3(1-pyrrolidinyl)-1-propanol
hydrochloride
used as antiparkinsonism
CH 3H
Synthesis of procyclidine:
+ HCHO + HN
O
CH 3
BrMg
BrMgO
Mannich
reaction
O
N
Grignard
reagent
Acetophenone
HO
Cl
N
H
amino amides:
O
H 3C
N
N

tropicamide: N-ethyl-NOH (4-pyridylmethyl)
tropicamide (or)
N-ethyl-N-(4-pyridylmethyl)
--phenyl--hydroxymethyl
acetamide
used as mydriatic agent
hydrolysis by HCl
N
Neuromuscular blockers.
non competitive depolarizing blockers
CH3
O
N CH 3
CH3
O
CH 3
N CH
3
CH 3
O
O
2Cl
choline cloride
succinate
Succinyl choline ( suxamethonium)
competitive non depolarizing blockers
O
N(Et) 3
3I
O
N(Et) 3
O
N(Et)3
Gallamine triethiodide