Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

1. Local Anesthetic

2. • Local anesthetics are drugs used to
reversibly depress CNS to prevent or
relieve pain in specific regions of the
body without loss of consciousness
• Unlike General Anesthetics, they
generally don’t block sense of touch,
pressure or temperature or relax
skeletal muscles

3. Uses
• Dentistry
• Podiatry (treatment of disorders of the foot,
ankle, and leg)
• ENT operations
• Surgery of skin
• Labor pain
• Postoperative pain
• Skin Trauma

4. How Nerve conduction occurs?
• Nerve conduction is a both electrical and
chemical component
• The electrical component occurs within the
axon. It involves membrane bound voltage
gated ionic channels (responds to change in
voltage across the membrane)
• The chemical component occurs at synapse.
It involves membrane bound ligand gated
ionic channel (responds to binding of a NT)

5. Chemical transmission of stimuli
occurring at synapse through NT
binding to their receptors
Electrical transmission of stimuli
occurring through axon by
movement of ion in and out

6. •When charges are separated by distance, potential difference is
created
•The inside of cell has more potassium and less Sodium and large
anionic Protein (A-) that cannot cross the lipid membrane and is
thus localized inside the cell
•The outside of the cell has more Sodium and less potassium
•This difference is maintained by Na/K pumps that pump in 2K+ ion in
cell and pump out 3Na+ ion out. Thus one extra positive charge out
•Overall, the inside of the cell has more negative charge and the
outside has more positive charge
•This gives the cell a resting potential of -70mV
Concept of potential difference and its generation (-70mV)
in resting cell

7. Events during an action potential
An action potential is a temporary “all or nothing” changes in cell membrane potential

8. Steps in a action potential
• (1) A stimulus from a sensory cell or another neuron causes
the target cell to depolarize toward the threshold potential.
• (2) If the threshold of excitation (-55mV) is reached, all Na+
channels open and the membrane depolarizes.
• (3) At the peak action potential (+30mV) K+ channels open
and K+ begins to leave the cell. The membrane starts to
repolarized. At the same time, all Na+ channels close.
• (4) The membrane becomes hyperpolarized (-90mV) as K+
ions continue to leave the cell. The hyperpolarized
membrane is in a refractory period and cannot initiate
another action potential
• (5) The K+ channels close and the Na+/K+ transporter
restores the resting potential (-70mV).

9. Changes in the resting membrane potential
Cell state Active receptors Potential
Resting potential Na/K Atphase pump active -70mV
Stimuli causes
Depolarization beyond
threshold potential (-55mV)
Voltage gated Na+ channel open
Na comes inside cell
+30mV
Repolarized state Voltage gated Na+ channel close
Voltage gated K+ channel open
K goes outside cell
+30 to -70mV
Hyperpolarized state Voltage gated K+ channel close slowly -90mV
Resting potential Na/K Atphase pump active -70mV

10. Mechanism of Action
• Local anesthetics work in general by binding to the
voltage gated sodium channel receptors inside the
cell and thereby inhibiting generation of action
potentials in the axon. Thus they reduce the
excitability of the neuron.
• The presence of large anionic proteins inside the cell
and Na/K ion pumps in the cell membrane , that
pump2 K+ intracellular for every 3 Na+ it pumps
extracellular, create a -70mV resting potential

11. Mechanism of Action (cont’d)
• If a stimuli depolarizes the resting potential to reduce
the membrane potential to less than -55 mV (ie it
goes towards +30mV) then a series of events occur
where membrane potential increases to +30mV and
back to -70mV.
• The first step of this entire process is opening of
voltage gated sodium channel which allows influx of
sodium ion to cause increase in membrane potential.
LA act here to block the Na influx and thus prevent
stimuli propagation through the axon

12. How LA primarily blocks pain?
• Different neurons carry different stimulus such as pain
• cold, warmth, touch and deep pressure.
• The neurons differ in the thickness of the axon
• Thin axons are most sensitive to drugs
• Neurons carrying pain has the thinnest axon
• Then comes cold, warmth, touch, deep pressure
• Thus effect of LA also follow this order
• Also nerve fiber are thinner than muscle fiber, thus
they are blocked preferentially and thus no muscle
relaxation occur with LA

13. Applications of LA
There are different ways to use LA depending on
site on application:
• Topical
• Infiltration
• Plexus block
• Epidural block
• Subarachnoid (spinal) block

14. • A topical anesthetic is a local anesthetic that
is used to numb the surface of a body part.
They can be used to numb any area of the skin
as well as the front of the eyeball, the inside
of the nose, ear or throat, the anus and the
genital area. Topical anesthetics are available
in creams, ointments, aerosols, sprays, lotions,
and jellies. Examples include benzocaine,
lidocaine, oxybuprocaine,

15. • Topical anesthetics are used to relieve pain and
itching caused by conditions such as sunburn or
other minor burns, insect bites or stings, poison
ivy, poison oak, poison sumac, and minor cuts
and scratches.
• In dentistry, topical anesthetics are used to numb
oral tissue before injecting a dental local
anesthetic to prevent pain due to the entry of the
needle into the soft tissues of the oral cavity

16. Infiltration
• It is the application of LA in intradermal or
subcutaneous layers
• Only the nerve fibers near the injected site is affected
• The adequate dosage required depends on
– the extent of the area to be anesthetized
– on the expected duration of the surgical procedure.
• Patients frequently experience pain immediately after
infiltration injection of local anesthetic solutions. This
response is due in part to the acidic nature of these
solutions.
• neutralization of LA solutions by addition of sodium
bicarbonate reduces pain
• Used for postoperative pain control at incision site and
suturing

17. Plexus block
• plexus or ganglion are a group of nerves that
transmits pain caused to a specific organ or body
region. Use of LA in these region causes analgesia
in the organs or region associated with it
• Brachial plexus blocks are employed for surgery
of shoulder, arm, forearm, wrist and hand.
• A celiac plexus block is performed for surgery of
the abdomen

18. The spinal cord run through a tunnel formed by bones of
vertebrae called spinal canal

19. The spinal cord is surrounded by a
sac (sac means bag, pouch)
containing a liquid called
cerebrospinal fluid.
This is the site of spinal block ie
right into this sac
Epidural block is given in region just
outside of this sac within the spinal
canal

20. Epidural block
• Application of LA in the epidural space, ie just outside
of the sac of cerebrospinal fluid, and thus blocking the
transmission of pain signals from peripheral sensory
neuron
Uses
• More effective and safe than N2O during labor pain
• Management of back pain for hospitalized patient
• As a supplement to general anesthesia so that use of
opiod analgesics can be avoided
• gynaecological surgery, orthopaedic (muscle n bone)
surgery, vascular (artery n veins) surgery

21. Spinal block
• Application of LA in the region containing cerebrospinal
fluid ,which holds the spinal cord, thus blocking the
transmission of pain signals from peripheral sensory
neuron
• Uses: Total Hip Replacement, Total Knee Replacement,
Caesarean sections, Lower limb Vascular surgery
• limited to procedures involving regions below the upper
abdomen.
• Use in higher levels may affect the ability to breathe by
paralyzing the intercostal respiratory muscles and the
disturb heart rate by paralyzing cardiac nerve fibres

22. Epidural vs Spinal
Epidural Spinal
Dose is high (10-20 ml) Dose is low (1.5-2 ml)
Onset is slow (25-30 min) Onset is fast (5 min)
does not cause as significant
neuromuscular block
Does cause as significant neuromuscular
block
Multiple dosing possible Single dose only
Can be given at various point along the
Backbone
Can only be given at specific point along the
Backbone to avoid damaging the spinal cord

23. Block vs Infiltration
• A block is placement of the local anesthetic
adjacent to a major nerve or a major branch of
the nerve that stops sensation from that point to
the terminal end of the nerve. Everything "down
stream" from where the block was placed will be
numb.
Infiltration is placement of local anesthetic near
(or in) the area you want anesthetized. Mostly it
affects the terminal branches of the nerves.
Typically, an infiltration will only affect that area
and not beyond. (thus it is the most localized LA!)

24. Local anesthetics used in eye only
Ophthalmic anesthetics are topical agents that act
locally to block pain signals at the nerve endings in the
eyes. They are available as eye drops, ointment and gels.
Uses
• Perform a applanation tonometry.(Tonometry
determines the intraocular pressure)
• Perform a Schirmer's test. ( Schirmer's test determines
whether the eye produces enough tears to keep it
moist)
• Remove small foreign objects from the uppermost
layer of the cornea or conjunctiva
Drugs used are Tetracaine 0.5% and Proparacaine 0.5%

25. Eutectic mixture of LA
• A topical anesthetic made from equal parts of lidocaine and
prilocaine which separately are solid but together take a liquid
form with melting point of 18oC
• This property where a mixture of substances having a melting
point lower than that of any of its components is called
Eutectic mixture
• Manufactured as a 5% oil in water emulsion containing 2.5%
each of lidocaine/prilocaine
• It is applied as a cream on unbroken skin, then covered with
an occlusive dressing, to kill pain prior to
– venipuncture, intramuscular injections, intravenous
cannulation,

26. Advantages over other topical LA
a) the local anesthetic bases are present in their permeable
uncharged forms;
b) water is used as the vehicle which is a poor solvent for
these drugs. This causes drug to rapidly saturated water (at
low concentrations) and then move on to act on the skin
c) Simply use of an oily vehicle would effect distribution
coefficients of the active substances between the skin and
the formulation
d) the droplets consist of dissolvable drug and act as reservoirs
to obtain steady-state release; and
e) the fluid state of the excess drug provides a higher
dissolution rate than from a solid state.

27. Local anesthetics and vasoconstrictors
• LA are removed from site of application due to
absorption into blood
• Vasoconstrictors increase the duration of local
anesthesia by constricting the blood vessels, so that
less blood flow and consequently less absorption into
blood occurs. Thus it allows LA to work for an extended
duration, as well as reducing hemorrhage. Examples
include:
• Prilocaine hydrochloride and epinephrine
• Lidocaine, bupivacaine, and epinephrine
(recommended final concentrations of 0.5%, 0.25% and
1:200, respectively)

28. The classification of local
anesthetics
Ester
• Cocaine
• Procaine
• Tetracaine
Amides
• Lidocaine
• Bupivicaine
Ether
• Pramoxine
Ketones
• Dyclonine

29. Structure Activity Relationship
• Most drugs are salts of weak
acids or weak bases
• But how to know by just
looking at structure if a drug is
acidic or basic?

30. Use of pKa?
• Pka can’t tell the difference of acid/base
• It only tells how strong an acid or base is but
doesn’t tell if it’s an acid or base
Paracetamol Pka is 9.5 but it is an acid
It is weaker acid than acetic acid those Pka is 4.5
Diazepam Pka is 3.4 but it is a base
It is weaker base than NH3 those pKa is 10

31. The key is to look for the specific
functional groups
• Acidic drugs contain one of these groups
• ALL Basic drugs contain Nitrogen as amine groups, (all
except quaternary amine) or double bonded to C
(C=N)
NH2 H3C
H
N
CH3H3C H3C
N
CH3
CH3
primary amine Secondary amine tertiary amine
H3C
N
CH3
CH3
quanternary amine
CH3
All basic to the same degree Not basic
OH
H2N
O
R
H3C
O
R
AmideAldehyde /ketonePhenol
R COOH
carboxylica acid
R

32. SAR of LA

33. • All local anesthetics have an amine on one end to an
aromatic ring on the other
• The amine end is hydrophilic, and the aromatic end is
lipophilic.
• The two groups are connected by mostly an ester or an
amide group and less commonly by ether or ketones
• Thus two main classes of local anesthetics exist: Amides
and Esters
• Esters have an ester link between the amine chain and
the aromatic end.
• Amides have an amide link between the amine chain and
the aromatic end
• They have pka in range of 7.5 to 9.5

34. • Esters and amino amides differ in metabolism,
stability and adverse effects
• Esters are metabolized in the plasma but Amides
are metabolized in the liver.
• Esters are unstable in solution, but amides are
very stable in solution.
• Esters are much more likely than amides to cause
allergic reactions

35. Lipophilic group
• Lipophilicity is important to penetrate the lipid layer and
reach the binding site on the inside of the cell
• Presence of electron withdrawing group in ortho or para
(not meta) position decreases Lipophilicity but still
increases activity for only ester group
O
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N
O
C
O
H2
C
C
H2
N
C2H5
C2H5
Procaine is more potent if it has a e- donating amine group in the aromatic ring
Procaine
Note: Other e donating groups in decreasing order are –OH > -NH2 > -
Oalkyl (OCH3) > -alkyl (CH3) (valid everywhere)
Less potent than procaine

37. • This increase in activity (valid for ester only) is
due to possibility of Zwitterionic form which
enhances activity due to formation of
quanternary amine which is important for
binding
O
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N
Procaine
O-
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N+
Zw itterioninc
form

38. What n when is ortho, para ,meta?
No substituion
No ortho, para
,m eta
CH3
Single substituion
Again, no ortho,
m eta, para
CH3
CH3
CH3 CH3
CH3
CH3
H3C
H3C
Only in bi-substituted there is
ortho, m eta and para
O rtho
M eta
CH3
CH3
Para

39. • Presence of e- withdrawing halogens in ortho
position only can decrease duration of action
by making the ester more Likely for a
nucleophilic attack
O
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N
Procaine
O
C
O
H2
C
C
H
2
N
C2H5
C2H5
H2N
Chlorine in ortho group makes the carbonyl carbon more
positive and more likely to be attacked by nucleophiles
that causes breakdown of compound.
Nucleophiles contain a lone pair of electron. They attack
atoms with positive charges. M ore positive the atom, the
better the attack
Cl
longer acting
shorter acting
chloroprocaine

40. • For amide only,
presence of di-ortho
substituted group
prevent breakdown of
amide and thus increase
it’s stability in both
liquid formulation and
the body enzymes
CH3
CH3
NH C
O
CH2 N
C2H5
C2H5
NH C
O
CH2 N
C2H5
C2H5
CH3 groups m ake it difficult to hydrolyze.
thus it is Stable in water and blood.
Sufficient duration of action
No protection against hydrolysis
by disubstituted group. Thus unstable
in water and blood. Not enough duration of action
Note: instead of CH3, other groups such as OCH3 can also be used

41. Linker group
• Linker group has short alkynene (-CH2-) chain
containing few carbon atoms and various
functional group such as Amides, Esters, Ether
or Ketones
• Increasing the length of alkylene chain
increases the pKa which reduces potency
because more drug get ionized outside the
membrane and thus can’t penetrate into the
binding site
Note: -CH2- group is called methylene, -C2H4- is called ethylene
-CH3 is called methyl, -C2H5 is called ethyl
CH4 is methane, C2H6 is ethane

43. Hydrophillic group
• Useful LA have a secondary or tertiary amine group
• This is important because it is believed that when
they enter the cell, they will accept a proton and
form positively charged quanternary form which is
needed for binding to voltage gated ion channels
O
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N
O
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N
H
charged Quanternary formis beleived
to bind to receptor
Procaine believed to bind to it’s receptor when the amine group is positively charge
quanternary form

44. • However, Benzociane has no anime portion
but is still an effective topical LA
• Thus the use of Amine part could only be for
proper water solubility and not directly
related to proper binding
O
C
O
CH2
CH3
NH2
Benzocaine has no amine
but is still effctive LA

45. PROCAINE
• Procaine is a local anesthetic drug of the ester group
• effective parental but are relatively weak when applied
topically
• slow onset (4-5 min), short duration, pKa=8.8
• Procaine has the advantage of constricting blood vessels*
which reduces bleeding, unlike other local anesthetics like
lidocaine
• is metabolized by the plasma enzymes to form para-amino
benzoic acid (PABA) which is causes allergic effect
• MOA – blocks pain by depressing CNS by antagonizing
votage gated Na+ channel thus inhibiting generation of
action potential
•This sud increase duration of action like with lidocaine and epinephrine but it can’t because
esters are such functional groups that get naturally quickly hydrolyzed/metabolized than other
functional groups such as amide, alcohol

46. Which is more lipophillic?
Which can exist as enantiomers?

47. Lidocaine
• Most commonly used potent amide type local anesthetic
for both parenteral and topical use
• has a rapid onset of action (Intravenous - 45 to 90 seconds).
and more lipid solubility than procaine, pka = 7.8
• Di-ortho methyl groups make the amide group resistant to
hydrolysis thus it has moderate duration of action (1-2 hrs)
• Produces eutectic mixture with prilocaine
• Class IB Antiarrhythmic function
• MOA – blocks pain by depressing CNS by antagonizing
votage gated Na+ channel thus inhibiting generation of
action potential

48. Bupivacaine
• A potent amide type local anesthetic used mostly
parenterally
• It has rapid onset of action and higher lipid solubility
and lower hepatic degradation and thus longer duration
of action (6-8 hrs) than the structurally similar lidocaine,
pKa = 8.1
• It exists in racemic form. The R isomer has greater
affinity for Voltage gated Na+ channels and is linked
with cardiotoxicity
• The S isomer, called levobupivacaine, is clinically used as
it has lower cardiotoxicity and CNS toxicity
• MOA – blocks pain by depressing CNS by antagonizing
votage gated Na+ channel thus inhibiting generation of
action potential

49. Procaine synthesis
H2N C
O
O H HO CH2CH2N(C2H5)2
H2SO4
-HOH
H2N C
O
O CH2CH2N(C2H5)2
HCl
Procaine
para- amino benzoic acid 2-D iethylamino-ethanol
H2N C
O
O CH2CH2N(C2H5)2.HCl
condensation
Procaine hydrochloride

50. Lignocaine synthesis
CH3
NH2
CH3
CH3
CH3
NHCO CH2ClCl.CO CH 2Cl
Chloroacetyl
chloride
2,6-D im ethyl-phenylam ine
D iethyl am ine
CH3
CH3
NHCO CH2N(C2H5)2
-H Cl
N H (C2H 5)2
Lignocaine
H Cl
CH3
CH3
NHCO CH2N(C2H5)2.HCl
Lignocaine Hydrochloride

51. Review
General Anesthetic Local Anesthetic
Blocks pain in entire body Blocks pain in specific region on body
Blocks sensation of temperature, touch and
pressure
Selective to blocking pain only.
Muscle relaxation occurs Muscle relaxation not caused
Drug intended to penetrate brain Drug not intended to penetrate brain but
act on local nerves branches
Receptor is ligand gated chlorine channel
and
Binding site is outside of cell membrane
Receptor is voltage gated Sodium channel
and
Binding site is inside of cell membrane

52. Chemical transmission of stimuli
occurring at synapse through NT
binding to their receptors
Electrical transmission of stimuli
occurring through axon by
movement of ion in and out

55. Q) Why LA only blocks pain?
Ans: Sensitivity to LA depends on
thickness of axon. Thinner neuron are
easily effected.
Neuron function Thickness (uM) Sensitivity to LA
motor 12-20 +
Touch , pressure 5-12 ++
Temperature 2-5 +++
Pain 0.4-1.2 ++++

56. MOA:
blocks Voltage gated Sodium channel -->
Prevent generation of action potential -->
blocks neuronal transmission of stimuli
(especially pain)

57. • What is a stimuli?
A thing or event that evokes a specific functional
reaction in an organ or tissue

58. Applications of LA
same drug can be used
• Topical - skin, eye or any body cavity (vagina,
nose, ear, interior surfaces)
• Infiltration – maximum localized LA, acts on finer
nerve branches
• Plexus block – blocks a major nerve branch and
its associated region
– Brachial plexus blocks are employed for surgery of
shoulder, arm, forearm, wrist and hand.
– A celiac plexus block is performed for surgery of the
abdomen

59. Block vs Infiltration

60. shoulder
arm
forearm
hand
thumb
fingers
Spinal cord
Left armRight arm
•Block used in major nerve branch
•Infiltration in minor/local nerve branch

61. Site of Epidural and Spinal block

62. Epidural vs Spinal
Epidural Spinal
Dose is high (10-20 ml) Dose is low (1.5-2 ml)
Onset is slow (25-30 min) Onset is fast (5 min)
does not cause as significant
neuromuscular block
Does cause as significant neuromuscular
block
Multiple dosing possible Single dose only
Can be given at various point along the
Backbone
Can only be given at specific point along the
Backbone to avoid damaging the spinal cord
•Epidural block is widely used in labor pain
•Spinal block used in Caesarean sections

63. SAR of LA
•Hydrophillic part imp for
penetration inside the cell to
reach binding site
•Hydrophillic amine group
binds to receptor in charged
Quanternary form

64. Ester Amide
relatively unstable than amides Relatively More stable than esters,
Metabolism by plasma enzymes Metabolism by liver
Allergic effect due to metabolic
production of PABA (para amino benzoic
acid)
No allergic effect of metabolic product
Presence of diortho methyl groups (or methoxy)
Increases stability of amides
Presence of amine in aromatic ring increases
Potency due to charge on nitrogen due to
Possibility of Zwitterionic form

65. O
C
O
H2
C
C
H2
N
C2H5
C2H5
H2N
O
C
O
H2
C
C
H2
N
C2H5
C2H5
Procaine is more potent if it has a e- donating amine group in the aromatic ring
Procaine
Note: Other e donating groups in decreasing order are –OH > -NH2 > -
Oalkyl (OCH3) > -alkyl (CH3) (valid everywhere)
Less potent than procaine

66. • All LA have Pka between 7.5 – 9.5
• Anything beyond this range and there will be
more ionization at pH 7 of the blood.
• More ionization blocks the penetration of
drug through the lipid membrane and they
can’t reach their biding site which in inside of
cell

67. CH3
CH3
NH C
O
CH2 N(C2H5)2
CH3
CH3
NH C
O
CH2 CH2
CH3
CH3
NH C
O
CH2 CH2 CH2 N(C2H5)2
N(C2H5)2
pKa = 7.8
pKa = 9.0
pKa = 9.5
A ll LA are basic drugs because
they contain am ine group
A s pKa increases, the drugs
becom e m ore basic and thus
m ore ionized in the blood
In ionized form , they can't cross
the lipid m em brane and reach
their binding site
increasing pKa = increased ionized form= decreased potency
Effect of increasing linker length in lidocaine
Increasing CH2 group = increased pKa (increased basicity) =
increased ionized form = decreased potency

68. CH3
CH3
NH C
O
CH2 N
CH3
CH3
NH C
O
CH2 N
C2H5
C2H5
C2H5
C2H5
H

69. Factors effecting Duration of action as by the SAR
Phenobarbital Thiopental Sodium
Branched R group
Short ethyl chain
Total carbon = 2 (not counting
aromatic)
Long chain of R group
Total C = 7
Additional improvements to
Thiopental Sodium tofurther
decrease duration of action
•N methylation (potency also inc)
•Unsaturated R group

71. Thank you
• This is a
“photo”
of a protein
(tertiary
Structure )
• It has 347 amino
acids

72. Same protein but shown
in helix( red )
and sheets (blue)
And loops

73. Same protein but
now there is a drug
binding to it

74. This is the binding
site of that drug

75. Only showing amino
acids of the binding
site
Remember: proteins
are made of amino acids

76. This is what the drug is doing in the
binding site--> making chemical bonds
with it