; : - :/ - 3 3

:/ 3 ;23
: 3

A X 4HO NNE -O PTY : H H.

3- .: 1;
 Classification of Autonomic Drugs

1.  Mimetics
a)  Sympathomimetics ; adrenomimetics
b)  Parasympathomimetics, cholinomimetics

2.  Blocking Agents

a)  Adrenergic blocking agents ; Sympatholytic;
Antiadrenergics
b)  Cholinergic Blocking agents;
Parasympatholytics, Antimuscarinic agents,
Cholinolytic (drugs that block Ach at the neuroeffector)
 .:/ /:13- 1 3;
;XMPASHOMIMESICR D ENOMIMESICR
D ENE GIC RSIMTLANSR D ENE GIC AGONIRSR
◦  RSIMTLASION OF RXMPASHESIC NE UOTR ACSIUISX

: ) ; ; :, :
:; ;
  CASECHOLAMINER
  NON CASECHOLAMINER

: : ; ; :
◦  : :; ; , ; :;
:; , :; ; :; ;:
:; ;
 .:/ /:13- 1 3; ;
-HEMIRS X )
; ; :;:
; :

◦  INSE ACS DI ECSLX VISH AD ENE GIC ECEPSO R SO ELICIS ERPONRE

◦  3NCLTDE /PINEPH INE AND O EPINEPH INE VHICH A E
NAST ALLX OCCT ING CASECHOLAMINER
◦  SHE E AMPLER ) APHAYOLINE E BTSALINE 3ROP OSE ENOL
LBTSE OL ;ALBTSAMOL AND .OBTSAMINE
◦  OMASIC COMPOTNDR SHAS CONSAIN O SHO HXD O XL
RTBRSISTENSR A E HIGHLX RTRCEPSIBLE SO O IDASION
/SHXLAMINE CHAIN ERRENSIAL SO AGONIRS ACSIUISX
◦  CASECHOLAMINE
◦  PHENXLESHXLAMINE DE IUASIUE CONSAIN APP OP IASE
RTBRSISTENSR SO IMPA S DI ECS ECEPSO ACSIUISX
! CASECHOL 2 G OTP IN SHE MESA AND PA A
PORISION OF SHE A OMASIC ING
! β 2 G P N SHE ESHXL AMINE PO SION OF SHE
MOLECTLE
! P ERENCE OF AMINO G OTP IN PHENXLESHXL
AMINE IR IMPO SANS FO DI ECS AGONIRS ACSIUISX
!  HE 2 G OTP RHOTLD BE REPA ASED
F OM SHE A OMASIC ING BX - ASOM FO
OPSIMAL ACSIUISX
! / NHANCED DI ECS ECEPSO ACSIUISX
P ERENCE OF 2 G OTP ON SHE β CA BON
! : EDTCED ECEPSO ACSIUISX BX SHE
P ERENCE OF -2 G OTP ON α CA BON
◦  RTBRSISTENSR ALSE D TG ACSIUISX
! ;MALL RTBRSISTENSR HXD OGEN MESHXL
G OTP P ODTCE α ECEPSO ACSIUISX E G
O EPINEPH INE
!  A GE RTBRSISTENSR IROP OPXL G OTP
P ODTCER BESA ECEPSO ACSIUISX E G
3ROP OSE ENOL
.:/ /:13- 1 3; ;
◦  :EMOUAL OF SHE PA A ( HXD O XL G OTP LEAUER
ONLX A α ECEPSO ACSIUISX / HENXLEPH INE

◦  HE MESA 2 G OTP IR ERRENSIAL FO DI ECS α

ECEPSO AND β ACSIUISX

◦  -ASECHOLAMINER A E INACSIUASED BX MESHXLASION OF

SHE MESA 2 G OTP CASALXYED BX CASECHOL O
MESHXLS ANRFE ARE - AND BX O IDASIUE
DEAMINASION CASALXYED BX
 .:/ /:13- 1 3; ;
◦  SHE RTBRSISTSED PHENXL MOIESIER SO P OUIDE RELECSIUE
AD ENE GIC AGONIRSR RELECSIUE β ECEPSO AGONIRSR

! E G ERO CINOL RS TCST E IN ESAP OSE ENOL AND

E BTSALINE

!  ( : ING IR NOS A RTBRS ASE OF -

! β AGONIRS SHAS CONSAIN SHIR ING RS TCST E SEND SO
HAUE BESSE ABRO PSION CHA ACSE IRSIC AND LONGE
DT ASION OF ACSION SHAN SHEI CASECHOL CONSAINING
COTNSE PA SR
.:/ /:13- 1 3;
beta receptor activity

ISOPROTERENOL
.:/ /:13- 1 3;
LPHA :ECEPSO CSIUISXA

PHENYLEPHRINE
 .:/ /:13- 1 3;
,ESA :ECEPSO CSIUISX

SALBUTAMOL/ALBUTEROL
4-[2-(tert-butylamino)-1-hydroxyethyl]-2-
(hydroxymethyl)phenol
Salbutamol
"  First selective βagonist to be marked
"  Bronchospasm, asthma and COPD
"  Ventolin (Glaxo Smithkline)
"  SAR: tertiary butyl group in salbutamol
(or albuterol) makes it more selective
for β -receptors
;ALBTSAMOL LBTSE OL
Salbutamol (INN) or Albuterol (USAN)
!  RELECSIUE β ECEPSO AGONIRSR
!  EPLACEMENS OF SHE MESA 2 OF SHE CASECHOL
RS TCST E VISH HXD O XMESHXL G OTP -2 2
!  IMP OUE O AL BIOAUAILABILISX
3 .3:/- - 3 1
.:/ /:13- 1 3; ;
 .:/ /:13- 1 3; ;
3NDI ECS CSING D ENE GIC GONIRSR
◦  -HEMICALLX ELASED SO SHE CASECHOLAMINER BTS SHEX
DO NOS INSE ACS DI ECSLX VISH AD ENE GIC ECEPSO R

◦  ECHANIRM) ENHANCE SHE ELEARE OF SHE

ENDOGENOTR NET ORS ANRMISSE EFFECSR RIMILA SO
CASECHOLAMINE

◦  / AMPLER INCLTDE ; AND

 .:/ /:13- 1 3; ;
◦  L XL RTBRSISTSION AS SHE α CA BON ADJACENS SO SHE AMINO
G OTP ESA DR DERS TCSION OF PHENOL AND PHENXL
COMPOTNDR AND INC EARER LIPOPHILIC CHA ACSE
CONS IBTSING SO P OLONGED ACSIUISX

◦  RTBRSISTSION VISH BTL X G OTP INC EARER DI ECS β

ECEPSO ACSIUISX

◦  α MESHXL G OTP INC EARER SHE EFFECSIUENERR OF

INDI ECS ACSING AGENSR

◦  P ERENCE OF NIS OGEN RTBRSISTENSR DEC EARER INDI ECS

ACSIUISX VISH RTBRSISTENSR LA GE SHAN MESHXL ENDE ING
SHE COMPOTND UI STALLX INACSIUE
INDIRECT-ACTING
ADRENERGIC AGONISTS
Which structure will enhance the effectiveness
of indirect receptors

AMPHETAMINE

TYRAMINE EPHEDRINE
 .:/ /:13- :/-/ :;
! Alpha adrenergic receptors
!  α 1 - vascular smooth muscle
!  α 2 - sympathetic nerve terminals as well as on
vascular smooth muscle
! Beta Adrenergic receptor
! β receptor – heart
! β 2 receptor – smooth muscle
! β 3 receptor – brown adipose tissue/promotes
lipolysis
"  α1 - stimulates phospholipase C activity
◦  vasoconstriction and mydriasis; used as
vasopressors, nasal decongestants

"  α2 - inhibits adenylyl cyclase activity

◦  reduce brainstem vasomotor center-mediated
CNS activation; used as antihypertensives,
sedatives & treatment of opiate dependence and
alcohol withdrawal symptoms)
SELECTIVE AND NON-SELECTIVE
α-ADRENERGIC AGONISTS
ADRENERGIC AGONIST
3MIDAYOLINE D ENE GIC :ECEPSO
AGONIRS
! 1ENE AL O MTLA)

IMIDAYOLINE

◦  RINGLE AMINO O MESHXLENE G OTP

◦  ENHANCE AGONIRSIC ACSIUISX IF
RTBRSISTSED VISH HALOGEN O RMALL G OTP
o PORISION
 ;/ /- 3 / 2
.:/ /:13- 1 3; ;
NON-SELECTIVE ALPHA
ADRENERGIC AGONISTS

XYLOMETAZOLINE OXYMETAZOLINE
decongestant
selectively agonizes α1 and
partially α2 adrenergic receptors
 NON-SELECTIVE ALPHA
ADRENERGIC AGONISTS

NAPHAZOLINE TETRAHYDROZOLINE
vasoconstrictor Derivative of imidazoline
 SELECTIVE ALPHA-1
ADRENERGIC AGONISTS
SELECTIVE ALPHA-1
ADRENERGIC AGONISTS

PHENYLEPHRINE

METARAMINOL METHOXAMINE
 SELECTIVE ALPHA-2
ADRENERGIC AGONISTS
!  Clonidine
– (Catapress)
! Vasoconstrictive activity

!  Methyldopa
◦  derivative of phenylethylamine
◦  SAR : an alpha methyl group in correct
config on the phenylethylamine nucleus
yields a compound with increase potency
at α2 receptors.
NON-SELECTIVE BETA
ADRENERGIC AGONIST
! Isoproterenol
◦  SAR : the propyl substitution on the N
atom gives no effect on α receptor.
! Acts on β1 – increase cardiac output
! Acts on β2 – bronchodilation
 SELECTIVE BETA-1
ADRENERGIC AGONISTS
! Dobutamine
! Viewed as analog of dopamine
! Act on both α and β receptor
! Treatment of CHF
! Given IV
 SELECTIVE BETA-2
ADRENERGIC AGONISTS
SELECTIVE BETA-2
ADRENERGIC AGONISTS
! Salbutamol
! SAR: replacement of meta-OH group of the
catechol ring with hydroxy-methyl moeity.

! Salmeterol
! Partial agonist and has similar potency with
isoproterenol
SELECTIVE BETA-2
ADRENERGIC AGONISTS
! Ritodrine
! Used to control premature labor
! Reverse fetal distress due caused by excessive
uterine activity
! Can be given orally
SELECTIVE BETA-2
ADRENERGIC AGONISTS
! Terbutaline
! Modification of the catechol portion of beta
agonist
! Resorcinol derivative
! Bricanyl
α-ADRENERGIC ANTAGONISTS/
α-ADRENERGIC BLOCKERS
ALPHA BLOCKERS
ADRENERGIC ANTAGONISTS

NON-SELECTIVE ALPHA
BLOCKERS
NON-SELECTIVE ALPHA BLOCKERS

! Phentolamine
! Reversible blocking agent
! Group attached to imidazoline ring dictates
whether an imidazoline is an agonist or
antagonist
! Treatment of hypertension
 Alpha Blockers
Chemistry :
α Adrenergic antagonists ( α blockers) have varied
structures
◦  ergot alkaloids (ergotamine)
◦  dibenamines (phenoxybenzamine)
◦  benzolines-imidazoline(tolazoline)
◦  quinazolines (Prazosin, Terazosin)
SAR
"  β- adrenergic antagonists (β- blockers)
are structurally similar to β agonists

"  The catechol ring can be replaced by

a variety of other ring systems without
loss of antagonistic activity.
Alpha Blockers

phenoxybenzamine

Terazosin

Prazosin
SELECTIVE ALPHA-1 BLOCKERS
 SELECTIVE ALPHA-1 BLOCKERS

PRAZOSIN

TERAZOSIN DOXAZOSIN TRIMAZOSIN

! Quinazoline group:
◦  Prazosin
◦  Terasozin
◦  Doxazosin

!  Structure: quinazoline ring-piperazine ring-acyl moeity

!  4-amino group at quinazoline ring – essential for alpha1
receptor affinity
!  Acyl group affects pharmacokinetic properties
SELECTIVE ALPHA-2 BLOCKERS
SELECTIVE ALPHA-2 BLOCKERS

YOHIMBINE - increased release of norepinephrine with

subsequent stimulation of cardiac beta-1 receptors
BETA BLOCKERS
2 Main Types of Beta Blockers
Comparison between Beta Agonist
and Beta Antagonist
Non-Selective - Blocker (1st Gen)
Structural Features of Propanolol
Variations of Aryl Part (Naphthalene Ring)
Selective -Blocker (2nd Gen)
"  If
the naphthalene ring is replaced by
a para substituted phenyl moeity, the
resulted compound are selective
1-blocker
Why Para Substitution?
SELECTIVE BETA-BLOCKERS

ATENOLOL METOPROLOL

BETAXOLOL
CHOLINERGIC DRUGS
CLASSES OF CHOLINERGIC
STIMULANT
CHOLINERGIC AGONISTS (CHOLINE
ESTERS)
Acetylcholine
◦  the natural endogenous mediator
◦  most potent cholinergic agonists
◦  an ester of acetic acid and choline
◦  a quaternary amino alcohol.
◦  Ach is unstable and quickly hydrolyzed
both in vitro and in-vivo.
◦  extremely short acting and usually is not a
satisfactory therapeutic agent.
!  Onium group is essential for intrinsic activity;

!  trimethylammonium group is the optimal

functional moiety for the activity
Cholinergic Agonist vs. Antagonist
 INDIRECT-ACTING
Cholinesterase Inhibitors
Indirect Acting Agonists are generally
Acetylcholinesterase inhibitor and are divided into 2
major classes :
1.  REVERSIBLE (short acting) agents - principally
carbamates (carbamic acid esters) such as
physostigmine and neostigmine

2.  IRREVERSIBLE (long acting) agents – principally

organophosphate esters such as isofluorophate
and echothiophate agricultural insecticides and
nerve gases.
Carbamates (Reversible)

Physostigmine
Carbamates (Reversible)

PYRIDOSTIGMINE

DEMECARIUM
Carbamates (Reversible)

Neostigmine
Reversible
acetylcholines
terase inhibitor

benzenaminium
 INDIRECT-ACTING CHOLINERGIC
AGONISTS

NONCOVALENT INHIBITORS (Reversible)

EDROPHONIUM TACRINE
(Myasthenia gravis) (Alzheimer dementia)
INDIRECT-ACTING CHOLINERGIC
AGONISTS

ORGANOPHOSPHATES (Irreversible)
INDIRECT-ACTING CHOLINERGIC
AGONISTS
ORGANOPHOSPHATES (Irreversible)

ISOFLUROPHATE TABUN

SARIN SOMAN
INDIRECT-ACTING CHOLINERGIC
AGONISTS

ORGANOPHOSPHATES (Irreversible)

MALATHION PARATHION
MUSCARINIC RECEPTORS
"  M1- secretion from salivary glands and
stomach
"  M2 - slow heart rate
"  M3 – smooth muscle contraction
"  M4 – enhances locomotion (in CNS)
"  M5 – in CNS
CHOLINERGIC ANTAGONISTS

ANTI-MUSCARINIC
 MUSCARINIC RECEPTOR ANTAGONISTS

M1 SELECTIVE

PIRENZEPINE
– for peptic ulcer
 MUSCARINIC RECEPTOR ANTAGONISTS

NON-SELECTIVE

ATROPINE
ATROPINE
◦  block the action of Ach at muscarinic or nicotinic
cholinoreceptors

Chemistry :

1.  Atropine an alkaloid obtained from the belladonna

plant, is the prototypical cholinergic antagonists
(anticholinergic agent)

◦  A portion of the atropine molecule is structurally similar to

Ach permitting the molecule to bind postganglionic
receptors. The structure has no intrinsic activity and its
bulky shape prevents Ach from binding to the receptor.
Scopolamine
1.  Synthetic anticholinergic agents (Dicyclomine,
Propantheline)
!  Bulky analogs of Ach

2.  Pharmacologic spectrum (cationic head):

◦  quaternary nitrogen – (positively charged nitrogen)
(Ipratropium) which reduces passage across the blood brain
barrier
◦  tertiary nitrogen ( Dicyclomine which permits a broader
volume of distribution.
Anticholinergic agent
(Synthetic Analogs)

Propantheline Dicyclomine
NICOTINIC RECEPTORS
"  Classified into two sub-types based on their
primary sites of expression:

1. muscle-type nicotinic receptors

- found at the neuromuscular junction
2. neuronal-type nicotinic receptors
- found at the autonomic ganglia
ANTI-NICOTINIC
Cholinergic Antagonists (Nicotinic receptor)
Curare
•  Extract from ourari plant
•  Used for poison arrows
•  Causes paralysis (blocks acetylcholine signals to
muscles)
•  Active principle = tubocurarine
MeO

Me
N
HO Me
H CH2
O

CH2
H
Me
O
H N OH
Tubocurarine
OMe
TUBOCURARINE
"  COMPETITIVE NON-DEPOLARIZING AGENTS
"  naturally occurring alkaloids, curare
"  bulky rigid molecules
"  principal active alkaloid in curare
"  closely related trimethylate derivative is
metocurine.

◦  structural feature: presence of tertiary-

quaternary amine - distance between the 2
cations is rigidly fixed at about 14 Α (twice the
length of the critical receptor binding moiety of
Ach)
Cholinergic Antagonists (Nicotinic receptor)
Analogues of tubocurarine
O O

C C
Me 3N(CH2) 10NMe3 Me3NCH2CH2 O CH2 CH2 O CH2 CH2NMe3

Decamethonium Suxamethonium

•  Long lasting •  Esters incorporated

•  Long recovery times •  Shorter lifetime (5 min)
•  Side effects on heart •  Fast onset and short duration
•  Side effects at autonomic ganglia
2.  NONCOMPETITIVE DEPOLARIZING AGENTS
include Succinylcholine (Anectine) and
Gallamine

◦  slender aliphatic molecules.

◦  do contain two quaternary nitrogens.
NICOTINIC RECEPTOR ANTAGONISTS
NEUROMUSCULAR BLOCKERS/
SKELETAL MUSCLE RELAXANTS
Depolarizing

DECAMETHONIUM

SUCCINYLCHOLINE
CHOLINESTERASE
REGENERATOR
Pralidoxime
"  2-PAM
"  usually as chloride or methiodide salts
"  belongs to a family of compounds
called oximes that bind to
organophosphate-inactivated
acetylcholinesterase.
Pralidoxime
"  It is used to combat poisoning by organo-
phosphates or acetylcholinesterase
inhibitors (nerve agents)
CENTRAL NERVOUS
SYSTEM DRUGS
1.  Anxiolytics and Hypnotics
2.  CNS Stimulants
3.  Drugs for Depression
4.  Drugs for Mania
5.  Antipsychotics
6.  Drugs for Seizures
7.  Anesthetics
8.  Opioid Analgesics
 Antiepileptic General Structure

O
C C
NH NH O CH2 NH2 C

Barbiturates Hydantions Oxazolidinediones Succinimides Phenacemide Glutethimide

O
R1 R3
R2 C
H2N NH2
C C
O N O
Urea
H
 I. ANXIOLYTICS and HYPNOTICS
A. Benzodiazepines

DIAZEPAM
Benzodiazepines

Chemistry

◦  Alprazolam, diazepam, lorazepam,

oxazepam, flurazepam, prazepam, midazolam

◦  Varying duration of action

◦  Agents with a OH group at position 3 are easily

metabolized by phase II glucoronidation and are SHORT
ACTING.
Short acting benzodiazepines (OH group at
position 3)
!  Easily metabolized by phase 2 glucoronidation

Oxazepam Lorazepam
◦  Agents lacking 3-OH group must undergo
considerable phase I metabolism, including 3
hydroxylation. These agents are LONG ACTING.
(Diazepam, Clorazepate and Triazolam)

◦  Most long acting agents form the intermediate

metabolite desmethyldiazepam w/c has a very long
half life. These agents can have a cumulative action.
Long acting benzodiazepines – lack 3 OH group

! Considerable phase 1 metabolism

Diazepam
Triazolam
Con t. (Benzodiazepines)

◦  electron attracting substituent at position 7 is required

for activity and the more electron attracting it is, the
higher is the activity.

◦  Positions 6,8,9 should not be substituted

◦  A phenyl at the 5 position promotes activity

!  Ortho(2) or Diortho(2,6) with electron attracting substituent (X),
activity is increased.
!  Para (1,4) substitution decreases activity greatly.
◦  The 2 (R2) carbonyl function is optimal for activity,
as just the nitrogen atom at position 1.

◦  The N substituent should be small.

 I. ANXIOLYTICS and HYPNOTICS

B. Barbiturates

PENTOBARBITAL
BARBITURATES
Chemistry:

◦  5,5-disubstituted derivatives of barbituric acid, a

saturated triketopyramidine

◦  two side chains in position 5 are essential for

sedative hypnotic activity(R1 and R2)
BARBITURATRATES

◦  long acting agents have a phenyl and an ethyl

group in position 5.

INCREASE LIPOPHILICITY AND METABOLISM RATE:

◦  Branched side chains
◦  unsaturated side chains
◦  side chains longer than an ethyl group
!  Increased lipophilicity leads to a shorter onset of action,
shorter duration of action and increased potency
 Barbiturates

Phenobarbital Amobarbital Secobarbital

Con t (Barbiturates)

◦  Replacement of the position 2 oxygen with sulfur

produces an extremely lipophilic molecule that
distributes rapidly into lipid tissues outside the
brain.
 Barbiturate Relatives

O H
!  Primidone H3C N
•  pyrimidinedione and not a barbiturate; 2

N
•  conversion leads to Phenobarbital in O H
vivo
Primidone

!  Glutethimide O H
•  a non barbiturate sedative hypnotic; H3C N
O
•  safe alternative to barbiturates to treat
insomnia
•  a schedule II drug due to dependency. Glutethimide
II. CNS STIMULANTS

XANTHINE

CAFFEINE
"  is a purine base found in most human body
tissue and fluids in other organism.
"  Derive from xanthine, caffeine and
theobromine
"  Xanthinuria - rare genetic disorder lack
sufficient xanthine oxidase, cannot convert
xanthine to uric acid.
III. DRUGS FOR PARKINSONISM

•  Levodopa
•  Carbidopa
•  Dopamine
III. DRUGS FOR DEPRESSION

A. Tricyclic Antidepressants

Prevents reuptake of
serotonin and NE
"  R1: Must have 2-3 carbons in side chain,
compounds without side chain or with 4 or
more carbons are inactive
"  R2: All are amines: primary, secondary,
tertiary
"  Only mono-, or di-Methyl or un- substituted
amines are active
"  -Ethyl or higher decreases activity and
increases toxicity
"  *Secondary amines show CNS stimulatory
properties
"  R3: Substitutions at the 3 position retains
activity
"  -Heterocyclic N can be replaced with C and
activity is preserved
"  NO other ring modifications can be
accepted
B. Serotonin-Specific Reuptake Inhibitors (SSRIs)
C. Monoamine Oxidase Inhibitors (MAOIs)
V. DRUGS FOR MANIA

Li2CO3
VI. ANTI-PSYCHOTICS

A. Phenothiazine
ANTIPSYCHOTICS
Chemistry

1.  Phenothiazines

◦  Chlorpromazine, thioridazine, prochlorperazine, trifluoperazine,

fluphenazine

◦  Must have a nitrogen containing side chain substituent on the

ring nitrogen for antipsychotic activity.

◦  The ring and side chain nitrogens must be separated by a 3

carbon chain; phenothiazines – antipsychotic
!  The side chains:
! aliphatic aminopropyl side chain
! piperidine
! piperazine derivatives. (Piperazine side chains confer the
greatest potency and the highest pharmacologic activity)
◦  Fluphenazine and long chains alcohol form
stable, highly lipophilic esters(enanthate,
decanoate) w/c possess markedly prolonged
activity.

◦  ring and side chain nitrogens separated by a 2

carbon chain have only antihistaminic or
sedative activity. (Phenothiazine antihistamine)
Phenothiazines

Chlorpromazine
Propyldialkylamino
side chain
Phenothiazines

Thioridazine
Alkyl piperidyl side chain
Phenothiazines

Trifluoperazine
Propyl piperazine side
chain
VI. ANTI-PSYCHOTICS

Butyrophenones
Haloperidol
◦  Chemically unrelated to phenothiazine but
have similar activity
VI. ANTI-PSYCHOTICS

C. Dibenzoxapine

for Schizophrenia
 VII. DRUGS FOR SEIZURES
ANTIEPILEPTICS (ANTICONVULSANTS)

1.  Older agents

◦  derivatives of long acting barbiturates(Phenobarbital,

primidone)
◦  hydantoins (phenytoin)
!  close structural relatives of barbiturates
!  cyclic monoacylureas ; weak acids

Phenobarbital Primidone Phenytoin

 Hydantoins
HYDANTOINS

Close structural relatives of barbiturates

1.  Only lacking the 6-oxo group and are cyclic

monoacylureas rather than diacylureas

2.  No carbonyl group - weaker organic acids than

barbiturates and thus their sodium salt (e.g.,
phenytoin sodium) generates stronger alkaline
solution R1
R2
NH
5 1
4 2
O 3 O
N
R
 R1
R2
NH
5 1
4 2
O 3 O
N
R3
Hydantoins
SAR of Hydantoins
"  bulky aromatic ring in position C5 that confers
usefulness in generalized seizures, partial
seizures and status epilepticus but not well for
absence seizures
 Oxazolidinediones
R1
R2
O
5 1
4 2
O 3 O
N
R3
Oxazolidinedione

Replacement of the N-H group at position 1 of

the hydantoin with an oxygen atom yields the
oxazolidine-2,4-dione system
 O O
H3C

H3C N
CH3
Trimethadione is useful for absence seizures. O

Trimethadione
SAR:
1. absence of bulky substituents at the C5 position -
useful in absence seizures.

2. excreted in the urine - very toxic

 Succinimides
R1
O R2 O
CH2 H 3C
HO 3 4
2 5 H 3C N
OH O 1 O
N H
O O
R3
Succinic acid Succinimides Ethosuccimide

R1
Resulted from a search for a less toxic version R2
of the OXAZOLIDINEDIONES by replacing O
5 1
the O with CH2 O
4 2
3 O
N

Ethosuximide R3
•  lacking bulky groups attached at C3 which Oxazolidinedione
corresponds to C5 in the other related
structures and thus is good for absence
seizures.
•  Major metabolites are inactive
 Valproic Acids

O O
CH3 H3C
OH ONa
CH3 H3C

Valproic acid Valproate sodium

•  Dialkylacetates
•  2-propylpentanoic acid
 ANTIEPILEPTICS
(ANTICONVULSANTS)
2.  Newer agents

◦  Iminostilbenes (carbamazepine)
!  amido-substituted tricyclic system ;
diphenylurea)
◦  Benzodiazepines (diazepam,
clonazepam,clorazepate)
◦  GABA analog (Gabapentin)
◦  Phenyltriazine derivative lamotrigine
◦  Dicarbamate felbamate
Iminostilbenes
"  Amidosubstituted tricyclic system ;
diphenylurea

Carbamazepine
Gabapentin Lamotrigine
(GABA analog) (Phenyltriazine)
 GENERAL ANESTHETICS
◦  Induce a combined state of analgesia,
amnesia, loss of consciousness,
inhibition of sensory and autonomic
reflexes and skeletal muscle relaxation.
GENERAL ANESTHETICS
Chemistry
1.  Volatile or inhalation Anesthetics
◦  Inhaled as vapors and gases
◦  Simple lipophilic molecules

Classification:
1.  inorganic agent nitrous oxide (N2O)
2.  nonflammable halogenated HC (halothane)
3.  ethers (methoxyflurane, isoflurane, desflurane)
VIII. ANAESTHETICS
A. Inhalational Anaesthetics
GENERAL ANESTHETICS
2.  Non-volatile or IV anesthetics

◦  IV,IM – aq. solution, aq. propylene glycol solution or

emulsion
Classification: Water soluble and short acting agents

1.  ultrashortacting barbiturates-thioariturate (thiopental,

methohexital,thioamylal

2.  cyclohexylamines (ketamine)

4.  benzodiazepines (diazepam, midazolam)

4. butyrophenones (droperidol) and opioid analgesics

(morphine, fentanyl)
VIII. ANAESTHETICS
B. Nonvolatile Anaesthetics

KETAMINE PROPOFOL
Non-Volatile and IV Anesthetic

Fentanyl
citrate

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Midazolam
 LOCAL ANESTHETICS
◦  Benzoic acid derivatives – esters developed from
cocaine
◦  Aniline derivatives – amides developed from
asogramine
◦  Phenols and aromatic alcohols

General format of the structure :

◦  Lipophilic center – carbocyclic or heterocyclic ring

system
◦  Hydrophilic center – secondary or tertiary amine
 LOCAL ANESTHETICS
1.  Ester type agents are generally short acting due
to rapid hydrolysis by plasma esterases. Ex.
cocaine, procaine, benzocaine and tetracaine

2.  Amide type agents are generally longer acting

and are metabolized in the liver. Ex. lidocaine,
prilocaine, mepivacaine, bupivacaine
VIII. ANESTHETICS
C. Local Anaesthetics

Ester Amide